Section 1 Aetiology and epidemiology
Uric acid is the metabolic end-product of the breakdown of purine nucleotides. It is poorly soluble so tends to accumulate in crystalline micro-deposits of monosodium urate (MSU) in and around joints and in soft tissues, where progressive build-up can lead to tophus formation.
Mobilisation of synovial urate deposits as a result of a change in plasma and hence interstitial fluid uric acid concentration, followed by recrystalisation in joint fluid, triggers an influx of activated neutrophils leading to acute gout.
Urate deposits generally build up over a number of years before acute episodes occur. This process requires ambient uric acid concentration in excess of its super-saturation point (0.42mmol/l) most of the time. A serum uric acid of 0.50mmol/l equates to a 0.4 per cent annual risk of acute gout, rising to 5 per cent above 0.54mmol/l.
The annual incidence of acute gout is around three per 1,000 in men and 0.2 per 1,000 in women, rising with age.1
Urate load depends on the balance between the production of uric acid, which is both diet-derived and endogenously produced, and its elimination.
Most mammalian species metabolise uric acid further to the more soluble allantoin. In man, the uricase enzyme exists in the genome, but is disabled by premature stop codons.2 Uric acid levels are 25 per cent lower in women than in men, partly as a result of better purine recycling.
Average uric acid levels in pre-menopausal women are 0.24, rising to 0.28mmol/l after the menopause.1 Women are not at risk of gout unless uric acid levels are consistently above the male reference range (0.23-0.42mmol/l).
A high intake of purine-rich foods, such as red meat, offal, shellfish, pulses and fermented drinks, increases circulating uric acid levels. Conversely, a high intake of dairy products offers a mild protective effect. Generally, however, the bulk of uric acid is endogenous.
Alcohol and obesity increase endogenous uric acid production as well as reducing renal clearance of uric acid (possibly mediated by raised lactate levels and hyperinsulinaemia respectively) and are therefore the prime targets for lifestyle intervention in the prevention of gout.
Rare single gene defects can affect uric acid metabolism, such as deficiency of the salvage enzyme HPRT, which removes purines from the uric acid pathway for reutilisation, resulting in the Lesch-Nyhan or milder Kelly-Seegmiller syndromes, but hyperuricaemia is multi-factorial in the overwhelming majority.
Reduced renal clearance of uric acid is one of the factors contributing to the familial occurrence of gout.
Uric acid excretion
Thirty per cent of uric acid elimination is via the gut, the rest is excreted in the urine. Reduced glomerular filtration and the effects of relative sodium depletion on renal handling of uric acid are thought to explain the hyperuricaemic effects of loop and thiazide diuretics. This makes these drugs major risk factors for gout, particularly in the elderly, when renal impairment often compounds their effects.
Other drugs and metabolites influence serum uric acid levels by an effect on uric acid handling by the proximal tubule transport channel URAT1, which normally results in the reabsorption of around 90 per cent of filtered uric acid.3
Factors affecting excretion of uric acid
Drugs/metabolites that reduce renal excretion of uric acid
- Thiazide and loop diuretics
- Aspirin (low dosage)
Drugs that increase renal excretion of uric acid
- Aspirin (high dosage, ie >4g/day)
Section 2 Diagnosis
Acute episodes of gout generally occur in overweight men and are usually characteristic. Joint inflammation, usually monarticular, becomes intense within a few hours, with marked erythema, swelling and searing pain.
Initial episodes, which in men generally occur in the late thirties or early forties, affect an MTPJ in more than half of cases, followed by a midfoot joint, ankle and knee in decreasing order of frequency.
It is important to enquire about family history, drug history and alcohol intake. Tophi are not normally present at initial presentation and are rarely seen in the ear cartilage, occurring more commonly in the pulp of the end of a digit or in an olecranon bursa.
Initial episodes affect an MTPJ in more than 50 per cent of cases
Serum uric acid levels are helpful in diagnosis, but are as much as 25 per cent lower during acute episodes and may need to be repeated between attacks to give a true reflection of urate load.
It is not always practical to obtain synovial fluid for testing, but joint aspiration is valuable if there is diagnostic uncertainty. Gouty effusions are usually very turbid, and leucocyte counts can be in excess of 50,000/mm3, matched only by septic arthritis.
Plentiful needle-shaped negatively bi-refringent crystals of MSU in the fluid of an affected joint by polarised light microscopy is strongly suggestive of gout, but other causes of arthritis can co-exist. Microscopy is helpful in distinguishing gout from calcium pyrophosphate crystal arthritis ('pseudogout').
Small whitish linear aggregates of MSU are sometimes visible to the naked eye in gouty effusions. Higher concentrations of these aggregates produce gouty 'milk', which may discharge from chronically affected joints, usually in the fingers. Large punched-out peri-articular bone erosions, caused by a chronic inflammatory reaction to synovial tophi, can be seen in the digits in patients with advanced chronic gout, but X-rays are rarely helpful in initial diagnosis.
Acute phase markers (ESR/CRP) may be raised in acute gout, with fever, but should arouse suspicion of septic arthritis.
The differential diagnosis of acute gout also includes reactive and psoriatic arthritis, both of which are common in men and can affect a single joint, but inflammation is generally less intense and less acute in onset than in gout.
Idiopathic inflammatory arthritis (rheumatoid, for example) does not normally cause diagnostic confusion, except in rare cases of polyarticular gout, usually in the elderly, often triggered by major metabolic stress (such as intercurrent infection or surgery), which causes uric acid levels to plummet.
X-ray demonstration of chondrocalcinosis is helpful in the diagnosis of pseudogout. Pseudogout too is generally monarticular, though has a later age of onset, rarely affects smaller joints, has a more even sex distribution and doesn't share the metabolic/lifestyle risk factors of gout.
Section 3 Treatment
The treatment of acute gout with NSAIDs is often made more difficult by co-morbidities (such as renal impairment, congestive cardiac failure and hypertension) and by potential interactions with other drugs, notably warfarin, ACE inhibitors and diuretics. Nevertheless, NSAIDs remain the mainstay of treatment of acute gout.
An NSAID at adequate dosage is usually rapidly effective. Its prompt use limits the duration of treatment necessary, so patients at risk of frequent attacks should be encouraged to keep a stock of NSAIDs to hand.
While NSAID-related GI and cardiovascular risks need to be carefully assessed, excessive caution entails a real risk of inadequate treatment of acute episodes. Gastric acid suppression with a proton pump inhibitor (PPI) is necessary in patients at increased risk of peptic ulceration and is a useful safeguard in patients on anticoagulants, although metabolism of warfarin is affected by some PPIs.
Diclofenac and other drugs with predominant COX2 activity, which do not inhibit platelet aggregation, can be a safer choice in patients on warfarin.
Studies suggest a range of NSAIDs at conventional dosages are of comparable efficacy to the 'industry standard' indometacin 50mg three times daily in the treatment of acute gout.
NSAIDs at conventional doses are just as effective as indometacin in acute gout treatment
Colchicine is less rapidly effective and the nausea and diarrhoea induced by a standard regimen (1mg followed by 0.5mg every four hours up to a cumulative dose of 6mg) are rarely acceptable and can be as hazardous as the side-effects of NSAIDs.
Large joint gout responds very well to intra-articular steroids, as does small joint gout if the patient is brave enough to consent. IM depo-steroids (for example methylprednisolone 80-120mg) or a reducing course of oral prednisolone can be helpful, though not always fully effective, second-line treatments.
A reduced dosage of colchicine (0.5mg three times daily), in combination with a cortico-steroid or a low dosage of NSAID, can be a useful strategy on occasion. It is important to avoid compounding acute attacks by making changes to medication during the attack that can bring about abrupt changes in uric acid levels, whether up or down (such as diuretics or allopurinol).
Section 4 Prevention
Prevention becomes important if acute episodes are becoming increasingly frequent or difficult to treat. Compliance issues and the fact that uric acid is mostly endogenously produced mean dietary manipulation alone is rarely enough to control gout, but weight reduction and a reduced alcohol intake can be effective for those willing to make lifestyle changes, as can a switch away from diuretic treatment, where feasible.
Prevention with allopurinol, which blocks uric acid production by inhibiting the enzyme xanthine oxidase (XO), usually works well. Side-effects are few; most commonly rash and very occasionally liver toxicity.
Cautious re-trial can be successful in those with a history of mild rash, but re-exposure should be avoided in those with more severe skin reactions.
Allopurinol has an important interaction with azathioprine and 6-mercaptopurine, which are partly metabolised by XO. Allopurinol is renally excreted, so should be used in reduced dosage in proportion to eGFR.
It is important to point out to patients the increased likelihood of acute episodes in the first few weeks of allopurinol treatment. That can be partly offset by co-prescribing low dosage colchicine (0.5mg twice daily) or a regular NSAID in modest dosage for four to eight weeks.
A reduced allopurinol starting dose of 100mg daily, or even 100mg on alternate days in patients with renal impairment, rather than the more standard 200mg, brings uric acid levels down less abruptly and can reduce the likelihood of acute episodes in the early stages of allopurinol treatment, especially in those with particularly frequent or refractory attacks.
Uric acid levels fall maximally one week after starting allopurinol, although standard practice is to check uric acid levels after four weeks and to adjust allopurinol dosage accordingly, aiming for a serum uric acid of 0.36mmol/l. There is not normally any advantage in reducing levels further.
Maintenance dosages of allopurinol are generally in the range 200-400mg/day. In those with a particularly high urate load, acute attacks of gout can occur for up to six months after plasma uric acid levels have normalised.
Drug-induced vasculitis can be associated with use of allopurinol
Other preventive treatments
The uricosuric agents, probenecid and sulfinpyrazone, can be used as a second-line therapy to control hyperuricaemia in allopurinol-sensitive patients. Adequate hydration is important, particularly early on, to avoid urate stone formation.
Uricosuric agents are ineffective in patients with a GFR of less than 30ml/min.
1. Cohen M, Emmerson B. Gout. In: Klippel J, Dieppe P (Ed). Rheumatology. London: Mosby-Year Book Europe Ltd, 1994.
2. Wu X, Lee C, Munzy D et al. Urate oxidase: primary structure and evolutionary implications. Proc Natl Acad Sci USA 1989; 86: 9,412-6.
3. Mount D, Kwon C, Zandi-Nejad K. Renal urate transport. Rheum Dis Clin North Am 2006; 32(2): 313-31.
4. Nuki G. Treatment of crystal arthropathy. Rheum Dis Clin North Am 2006; 32: 333-57.
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