Gout

Gout is part of the hyperuricemia spectrum. It is a disorder of purine metabolism. Urate crystal deposition occurs in joints, soft tissues and renal tract; gouty arthritis is due to urate precipitation in joints. The most common joints affected are the first MTPJ (50-70% site of first presentation; podagra), other toes, ankles, knees and DIPJs. Polyarticular gouty arthritis is not uncommon (more likely in females).

Hyperuricemia spectrum:
1. Asymptomatic hyperuricemia
2. Acute gouty arthritis
3. Interval gout
4. Chronic tophaceous gout / chronic gouty arthritis

90% of people with hyperuricemia are under-excretors; 10% are over-producers, and a minority are both. 2/3rds of uric acid are excreted by the kidney; the rest by the GIT (bacterial degradation). Hyperuricemia is considered when urate levels are >0.42 mmol/L (7 mg/dL) in men and >0.36 mmo/L (6 md/dL) in women (post-menopausal, levels increase to male levels due to loss of estrogen-mediated excretion of uric acid), but levels do vary with patient build (and of course, population reference ranges).

Uric acid is the final product from purine (adenine, guanine) metabolism. The bulk of purines are endogenous; dietary purines account for a tiny percentage of the purine pool. Along the way of nucleotide and purine metabolism, the compound xanthine is produced, which by way of the enzyme Xanthine Oxidase, uric acid is formed.

Most people with hyperuricemia remain asymptomatic; presentations in symptomatics may include gout, renal stones, and uric acid.

Causes of hyperuricemia:
1. Under-excretion: primary hyperuricemia, renal impairment, hypertension, hypothyroidism, drugs (low-dose aspirin, thiazide diuretics, loop diuretics, cyclosporin), alcohol, ketoacidosis, lactic acidosis.
2. Over-production: primary hyperuricemia, dietary intake, excess turnover (psoriasis, tumor lysis syndrome, myelo-/ lymphoproliferative disorders), drugs (cytotoxics, vitamin B12), alcohol, excessive muscle exertion.
3. Combined/multifactorial: Glucose-6-phosphatase deficiency, obesity?, DM?, CAD?, CRF?, hypercholesterolemia/hypertriglyceridemia?, metabolic syndrome?

Asymptomatic hyperuricemia is 10 times more common than gout.

Five-year cumulative incidence of gout categorized by plasma urate level or serum uric acid level 

Features of gout:
1. Acute onset (<24hrs) MA. Red, shiny, swollen, hot joint, usually 1st MTPJ. Extremely tender to touch.
2. Usually subsides spontaneously in 3-10 days.
3. More of a disorder in men, and onset is earlier in men than in women.
4. Onset before age 30 may be due to renal or enzymatic disease, and may need specialist referral and more aggressive management.
5. 20% have a FHx of gout.

Diagnosis:
1. Typical history. Examination depends on stage of time course of acute attack.
2. Synovial or tophaceous fluid aspiration for demonstration of uric acid crystals (needle-like, negative birefringence under polarized light) is the gold standard for diagnosis, but may not be available everywhere or practical.
3. Exclude sepsis - as strep and staph can co-occur, send samples for MC&S & gram stain.
4. Presence of tophi.

Investigations:
1. During acute attack, uric acids may be normal (up to 30% of cases) and does not influence management.
2. FBC, U&Es, TFTS, B12, inflammatory markers may be useful; see above.
3. Uric acid should be measured 4-6 weeks after acute attack; this is to guide risk stratification and  subsequent management.
4. X-rays may be reserved for specialist management, or in diagnostic doubt (majority are normal; may see punched out erosions).

Differential:
1. Septic arthritis
2. Pseudogout (CPPD disease, calcium phosphate crystallopathy)
3. OA
4. Psoriatic arthritis
5. Reactive arthritis
6. RA
7. Seronegative spondyloarthropathy
8. Hemochromatosis

Initial Mx of acute attack:
1. Rest, ice.
2. NSAIDs (w/w/o PPI) .
3. Colchicine 500mcg bd-qds (avoid: renal impairment, CHF, elderly, bone marrow disease, liver failure. Anti-mitotic activity. Raises pH, preventing uric acid deposition. Can cause GI Sx, rarely bone marrow failure, myopathy, neuropathy, stimulation of vasomotor centers and vasoconstriction).
4. Steroids (PO prednisolone tapering dose, IM or intra-articular).
5. Continue allopurinol if already established on this.

Long-term Mx:
1. Lifestyle: Reduce weight gradually, reduce purine-rich foods (organ meats, red meat, sardines, herring, shellfish, asparagus, oatmeal, beans, mushrooms etc.; evidence level B - better to reduce total daily purine intake rather than absolute absolution), exercise (swimming, walking), consume atleast 2L of water (evidence level B), avoid excess alcohol.
2. Medication: Following a single attack, 40% will not experience another attack within a year; however, by three years, 80% will suffer a second episode. Thus, offer or at least make aware need for longer-term treatment. Aim to lower serum urate to <0.3 mmol/L.
3. Tophi may remain, enlarge, or disappear with long-term anti-urate therapy.

Long-term medication:
1. Allopurinol / XO inhibitors: Consider if two or more attacks in a year. Start at 50-100mg/day, and titrate slowly upwards until target serum urate level is reached (100-200mg in mild; 300-600mg in moderate and 700-900mg). Co-administer colchicine or NSAIDs, or 5-10mg prednisolone/day for 4-12 weeks. Can cause minor rash, or severe allergy/exfoliative dermatitis.
2. If allopurinol is not tolerated, consider a uricosoric like probenecid (500mg to 1g od) or sulfinpyrazone (100mg/day --> 600mg/day over 4 weeks) if there is no nephropathy, nephrolithiasis, or primary hyperuricemia.

Refer:
1. If diagnosis is in doubt.
2. Sepsis is suspected.
3. Oral medication is not tolerated, or intra-articular steroids are needed (and cannot be performed in primary care).
4. Young men or premenopausal women.

References:
NHS CKS
British Society for Rheumatology guidelines 2007
Evidenced-based diagnosis of gout