Syndrome associated with an elevated serum urate concentration and recurrent attacks of acute arthritis in which monosodium urate (MSU) crystals are deposited in the joint(s), synovial membrane, articular cartilage, ligaments and bursa. It is one of the most common causes of acute monoarticular arthritis. Also manifests as tophi (MSU in other soft tissues), gouty nephropathy and uric acid nephrolithiasis. Affects up to 3% of population – mostly males >40yrs and postmenopausal females. Higher prevalence in some ethnic groups (eg Maori and Polynesian populations).
Aetiology:
Depends on two processes – underexcretion of urate (more common) and overproduction of urate (less common).
Specific enzyme defects have been found in 1% – eg deficiency of hypoxanthine-guanine phosphoribosyltransferase and over activity of phosphoribosylpyrophosphate synthetase.
Risk factors predisposing to acute attack:
Drugs (underexcretion of urate is caused by diuretics, aspirin, ethambutaol, pyrazinamide, nicotinic acid, alcohol); recent surgery; obesity; postmenopausal (oestrogen increases uric acid excretion); severe psoriasis; alcohol; diabetes insipidus; Down syndrome; sarcoidosis; hyperparathyroidism; purine rich diet; kidney stone disease; chronic renal disease; renal transplant; rapid weight reduction; infections; hypertension (up to 1/3 develop gout)
Classification :
1) Primary Gout
a) Molecular defects undefined:
b) Associated with specific enzyme defects:
PP-ribose-p synthetase variants
HGPRT deficiency-partial (Kelley-Seegmiller syndrome)
2) Secondary Gout
a) Associated with increased De Novo Purine Biosynthesis:
HGPRT deficiency-complete
b) Glucose-6-phosphatase deficiency (glycogen storage disease, type 1)
c) Fructose-1-phosphatase aldolase deficiency
d) Associated with increase ATP degradation
e) Associated with increased nucleic acid turnover
f) Associated with decreased renal excretion of uric acid
3) Idiopathic Gout
No definable cause
Pathogenesis:
Two features necessary for an “attack of gout”:
1) Deposition of monosodium urate crystals in joint
2) Local inflammatory response to the crystals
Clinical features:
4 stages:
1) Asymptomatic hyperuricaemia
Serum levels of urate >7.0mg/100ml (0.42mmol/l) for males and >6.0mg/100ml (0.36mmol/l) for females is considered hyperuricaemic (defined as 2 standard deviations from the population mean). Have no symptoms of gout, but at higher risk of developing it. Many people have hyperuricaemia for a prolonged period of time and do not develop gout – can be as long as 20-40 years. Are at increased risk for nephrolithiasis. Treatment almost always not required, as most do not develop gout. Other factors that further predispose to gout should be addressed to lesson risk of developing acute attack (eg diet, hypertension).
2) Acute gouty arthritis
Usually occurs around 40-60 years (if <25yrs, could be unusual form of gout, eg enzyme defect); single joint usually affected in 85-90% of cases – 70% in the first metatarsophalangeal joint (podagra), but midtarsal region or heel is next most common site (and often missed), followed by ankle and knee; sudden and dramatic onset (few hours) acute pain, hot, swollen, tender joint (resembles cellulitis), limitation in range of motion – classically in evening or early morning; some have short history of mild pain (eg first MPJ; heel pain) prior to attack; 10%-15% are polyarticular; occasionally develop lymphangitis;. Symptoms subside in 1 –2 weeks if untreated; may get desquamation of skin over affected joint with resolution; polyarticular onset is more likely in females. Onset before age 30 in males or before menopause in females is atypical could be inherited enzyme defect or associated with renal disease.
3) Intercritical/interval period
Asymptomatic period between acute episodes – last from months to years (some never have another attack). After first ‘attack’ 2/3rd 2nd attack within 1 year – 90% have second attack with 5 years. Duration of intercritical period shortens and attacks become more severe with time. Prophylactic therapy usually used.
4) Chronic tophaceous gout
Chronic polyarticular gout synovitis; joint destruction; deformity; no pain-free intercritical period. If left untreated severe impairment and deformity. Average of 11 years from first attack to chronic tophaceous gout in those that develop it.
Tophi – tense shiny thin skin overlying the tophus (due to deposits of tophi in skin) may ulcerate may exude chalky white substance (monosodium urate crystals). Tophi do not develop unless there is a long history of gout – up to 10 years.
Laboratory:
Synovial fluid – polarised microscopy for urate crystals (present in 85%)
• Blood – high PMNL count; raised ESR; uric acid levels may be increased (often normal during acute attack in up to 30%); if secondary to renal disease creatinine and urea nitrogen will be increased.
• Elevated serum levels of uric acid is not diagnostic
Differential diagnosis:
Inflamed bursa; haemoarthrosis; atypical rheumatoid arthritis; seronegative spondyloarthritis; infective process. Most important is differentiating from infective/septic arthritis.
Possible reasons for first metatarsophalangeal joint being predominantly affected (more than 90% eventually have the first MPJ affected):
• higher prevalence of osteoarthritis (maybe subclinical) in this joint – as exposed to trauma of weightbearing
• lower temperature of foot joints (approximately 29°C) compared to body core body temperature (37°C) – uric acid is saturated at 32°C – . As most attacks occur at night, the temperature of the foot may lower more than the rest of the body or more rapidly than the rest of the body.
• relatively lower pH
While the first MPJ is the classic site for foot involvement, it can present in other foot joints (especially the midfoot) and as periarticular involvement at the insertion of the achilles tendon and plantar fascia – differential diagnosis of this can be aided by the good response of gout to colchicine. Deposition of crystals in the plantar aponeurosis heel pain.
Kidney disease:
• Urate nephropathy – from deposition of MSU in renal tissues mild proteinuria
• Uric acid nephropathy – precipitation of uric acid crystals in collecting ducts renal failure
• Uric acid nephrolithiasis – uric acid stones
“Diuretic” Gout:
This atypical form of gout develops in older age groups with renal impairment and high doses of diuretics very high levels of uric acid. Develop tophi very early in disease.
Diagnosis:
American College of Rheumatology criteria:
1) Urate crystals in the joint fluid, or
2) Tophus containing urate crystals
3) Any 6 of the following 12 criteria:
> 1 attack of acute arthritis; maximal inflammation developed within one day; monoarthritis attack; redness over observed joint; first metatarsophalangeal joint attack; unilateral tarsal joint attack; suspected tophus; hyperuricaemia; asymmetrical swelling of joint on x-ray; subcortical cysts without erosions on x-ray; joint fluid culture negative for organism during attack.
X-ray:
Asymmetric soft tissue swelling, tophi and erosions; ‘Rat bites’ – punched out lesions or erosions at joint margins (from tophaceous deposits). Martel’s sign – overhanging margins of erosions; normal mineralisation and joint space – but late in disease get some osteoporosis and joint space narrowing. However, as osseous changes do not appear for up to 10 years after the initial attack and the current successful management do not often see the classic radiographic changes today.
Radiographic changes in rheumatoid arthritis and gout (after Resnick , 1989):
Gout Rheumatoid Arthritis
Distribution Asymmetric joint involvement Symmetric joint involvement
Soft tissue swelling Eccentric Fusiform
Soft tissue calcification Occasional Rare
Osteoporosis Absent or mild Moderate or severe
Joint space loss Frequently absent Symmetric – occurs early
Bone erosions Eccentric
Frequent sclerotic margin
Intra- and extra-articular Marginal
Rare sclerotic margin
Intraarticular
Malignment Rare Common
Management:
Cold/ice packs can be used during acute attack to reduce pain and inflammation.
Splints to immobilise painful joint will help to reduce pain.
Local nerve block may be considered.
Management of co-existent and associated diseases (eg renal impairment, diabetes, obesity)
Drug management:
1) Symptomatic treatment – (eg colchicine, indomethacin, naproxen, etoricoxib). Colchicine most effective if given within first 24 hrs to stop attack – it is more specific for gout, but more toxic. Corticosteroids may be considered if NSAID’s contraindicated (eg renal failure, peptic ulcers) – acute attacks can respond well to an intra-articular corticosteroid.
2) Prevention of urate synthesis (eg allopurinol- inhibits xanthine oxidase – one dose a day)
3) Increase elimination of urate (eg probenecid, sulphinpyrazone – up to 4 doses a day)
Low doses of colchicine can also be used to prevent acute attacks, especially when there is a high risk of an attack that can occur during the implementation of other urate lowering drugs – but long-term therapy has high risk of toxicity.
Diet (often neglected due to efficacy of drugs) – avoidance of purine high foods:
• very high purine foods mussels, sardines, yeast, liver
• high purine foods anchovies, bacon, beef, crab, lobster, mutton, trout, turkey, veal, venison, scallops, alcoholic beverages.
• weight reducing diet
• increased intake of liquids
Surgical:
• surgical excision of tophi, especially if over weightbearing areas or is compressing important structures or is infected.
• fusion/arthrodesis of involved or damaged joints
• arthroscopic debridement of ankle and first MPJ has been shown to be of help
Podiatric management:
often first health professional to suspect its presence differential diagnostic skills (colchicine can be used as part of differential diagnosis if presentation is atypical eg midfoot, heel)
orthoses, splints and footwear modification to restrict joint range of motion
patient education
Case has been reported of peripheral neuropathy and foot ulcer as a result of prolonged allopurinol therapy .
Related Topics:
Uric Acid | Managing Gout in Primary Care
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