· heterogeneous group of diseases characterised by
· hyperuricaemia (increased serum urate)
· recurrent attacks of acute arthritis
· diagnosis confirmed by finding crystals of monosodium urate in synovial fluid
· other features
· tophi (deposits of monosodium urate in soft tissues)
· renal disease / stones
· disease of adult men
· M:F = 20:1
· peak incidence 40-60 yrs
· hallmark and prerequisite is hyperuricaemia
· uric acid level determined by balance between production and excretion
· produced by breakdown of nucleic acids (DNA and RNA)
· by oxidation of purine bases (guanine and adenine)
· converted through inosine, hypoxanthine and xanthine to uric acid
· 2/3 excreted into urine and 1/3 excreted into GIT
· uric acid filtered at glomerulus, reabsorbed in proximal tubule and secreted in subsequent proximal tubule
· hyperuricaemia due to a heritable error of metabolism
· 95% of cases
Overproduction
· 10% of primary gout
· due to disturbance of purine biosynthesis
· usually idiopathic
· some specific enzymatic causes known (eg. Lesch-Nyhan syndrome)
Underexcretion
· 90% of primary gout
· due to disturbance of renal excretion of uric acid
· due to other acquired disorders
· may be overproduction or underexcretion of uric acid
· causes include
· myeloproliferative disorders and reticuloses
· chronic haemolytic states
· drugs (diuretics, salicylates, pyranzinamides)
· starvation
· ketoacidosis
· acute alcoholism
· chronic renal failure
Lesch-Nyhan syndrome
· rare disorder
· X-linked recessive
· absence of enzyme in purine pathway
· leads to excessive uric acid formation and gout
· affects young boys
· mental retardation
· prone to self-mutilation
· sustained hyperuricaemia leads to development of monosodium urate monohydrate deposits in synovial lining cells and in cartilage on proteoglycans
· urate crystals released into synovial fluid
· may be due to
· trauma
· proteoglycan turnover
· unequal resorption of water and urate from synovial fluid
· sufficient number of crystals in joint precipitates attack by
· phagocytosis of crystals by leucocytes with release of chemotactic protein
· activation of kallikrein system
· activation of complement
· disruption of lysosomes within leucocytes with cell rupture and lysosome release into the synovial fluid
· tophi of monosodium urate monohydrate crystal aggregates deposited in synovium, cartilage and tendon sheaths
· lead to cartilage destruction and periarticular cyst formation
· 4 stages
1. initially there is asymptomatic hyperuricaemia
2. then there is the first attack of acute gouty arthrititis
· when this settles, hyperuricaemia persists
3. then there are recurrent attacks
· frequency of attacks of gout varies
· may become more frequent
4. eventually chronic gouty arthritis develops with joints no longer recovering from acute attacks
· arthritis and tophi develop
· in men vulnerable to classic gout, hyperuricaemia begins at puberty
· in women, starts at menopause
· risk of developing gout increases with
· serum urate level
· duration of hyperuricaemia
· usually develops after 20-30 years
· only 5% of hyperuricaemic patients develop gout
· predominantly affects distal lower extremity
· usually initially in 1st MTP joint (70%) (podagra)
· may also involve
· other joints in foot
· ankle
· knee
· hands
· usually monoarticular
· rapid onset of excruciating pain usually at night
· hot red shiny swollen joint
· very painful to touch
· may be accompanied by systemic features (fever, leucocytosis, raised ESR)
· takes days or weeks to resolve
· pain-free intervals of variable length
· onset may be spontaneous
· may be precipitated by
· trauma
· excessive activity
· dietary excess
· alcohol consumption
· diuretics
· systemic illness
· surgery
Arthritis
· after repeated attacks of gout
· asymmetrical destructive arthropathy
· often involves small joints in hand
· in 20% of cases
· white mass of sodium urate crystals
· visible underlying thinned-out skin
· may necrose overling skin and discharge
· involve
· periarticular subcutaneous tissue
· helix of ear
· along tendon sheaths (esp. Achilles)
· olecranon and prepatellar bursae
· in 15% of cases
· radiotranslucent uric acid stones
· may lead to renal failure
Serum uric acid
· attacks of gout occur when levels of serum uric acid change
· not necessary to have elevated serum urate during attack of acute gout
· elevated serum urate in patient with painful joint not diagnostic of gout
· elevated serum urate should be established in intercritical period
Synovial fluid
· specimen must be anticoagulated
· monosodium urate crystals diagnostic if found in synovial fluid
· does not exclude the presence of another arthropathy (including infection)
· characteristic needle-shaped crystals on microscopy
· lying free or in polymorphs
· negatively birefringent under polarised light and first-order red compensator
· appear bright yellow when parallel to compensator
· synovial fluid analysis typically shows WCC of 1000 to 70000 per ml with predominantly neutrophils
Tophi
· specimen should be fixed in absolute alcohol
· crystals disperse in formalin
· characteristic negatively birefringent crystals seen
· changes evident with chronic gouty arthritis
· usually in feet in heads of phalanges
· characteristic periarticular bony defects with punched out lytic appearance and overhanging sclerotic margin
· also see joint space narrowing and secondary osteoarthritis
· pseudo-gout
· septic arthritis
· acute bursitis
· cellulitis
· rheumatoid arthritis
· osteoarthritis
· psoriatric arthritis
· Reiter's disease
General
· rest, elevation and ice to joint
· analgesia (often narcotic)
Colchicine
· inhibits activation of inflammatory mediators by crystals
· very effective and rapid response strongly suggestive of diagnosis
· 1 mg then 0.5 mg q2h
· administered until
· patient improves
· GIT side-effects (esp. diarrhoea) occur
· maximum dose of 6 mg reached
· 80% of patients unable to tolerate optimum dose because of GIT side-effects
Non-steroidal anti-inflammatories
· usually better tolerated than colchicine
· indomethacin most commonly used
· dose is
· 75 mg stat
· 50 mg q6h until relief and another 24 hrs
· 25 mg q8h for 48 hrs
· side-effects include
· GIT toxicity
· sodium retention
· CNS disturbance
· naproxen and piroxicam also effective and have less side-effects, esp. in elderly
Glucocorticoids
· oral prednisone where
· colchicine not tolerated
· NSAIDs contraindicated (peptic ulcer disease)
· intra-articular steroids may be used for severe monoarticular attack
· esp. knee
· likelihood of recurrence can be reduced by
· weight loss and adequate fluid intake
· avoidance of known precipitating factors
· prophylactic daily colchicine 1-2 mg/day
· antihyperuricaemic drugs
Antihyperuricaemics
· absolute indication
· renal disease caused by uric acid stones
· relative indications
· three or more attacks of acute gout per year
· polyarticular gout
· one or more tophi
· uric acid > 500 mmol/l
· use drugs that
· increase renal uric acid excretion (probenecid, sulfinpyrazole)
· decrease uric acid synthesis (allopurinol)
Allopurinol
· inhibits xanthine oxidase
· short half-life but metabolised to oxipurinol which is also inhibitor of xanthine oxidase but has longer half-life
· dose is 300 mg/day (150 mg/day in patients with significant renal impairment)
· significant side-effects occur in 20%
· include rash, alopecia, bone marrow supression, hepatitis
· causes decrease in serum uric acid and this may precipitate acute attack of gout
· initiation of therapy should be accompanied by colchicine or NSAIDs