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Block 2 - MSK > GOUT - ONLINE MATERIAL > Flashcards

GOUT - ONLINE MATERIAL Flashcards

1
Q

Origins of uric acid

A
  • purine base
  • derived from breakdown of purine: adenine, guanine, hypoxanthine
  • also from breakdown of nucleoside (Adenosine, guanosine, inosine)
  • also from breakdown of purine nucleotide: ATP, ADP, AMP, GTP, GDP, GMP, IMP
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2
Q

Xanthine oxidase

A
  • converts hypoxanthine and xanthine into uric acid

- useful therapeutic target

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3
Q

Serum urate concentraiton

A
  • Males: 0.25 - 0.42 mM
  • Females: 0.18 - 0.38mM
  • solubilityof urate and crystalization are at 0.4mM
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4
Q

Uric acid levels depend on rates of

A
  • purine nucleotide syntehsis
  • purine breakdown
  • purine intake
  • uric acid excrtetion
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5
Q

Dietary origins of uric acid

A

Foods high in purines: seafood, meats, alcoholic beverage (esp beer)

Foods low in purine: Fruits, vegetable, grains, dairy, eggs

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6
Q

Uric acid production: de Novo pathway

A
  • purines are synthesized on a ribose phosphate backbone
  • becomes PRPP -> promotes high uric acid levels
  • PRPP has a positive feed-forward effect
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7
Q

Salvage pathway

A
  • divert purine base drom uric acid sunthesis and replenish nucleotide pool
  • uses two enzymes: APRT and HGPRT
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8
Q

Role of salvage pathway enzymes

A
  • minimize uric acid production
  • recover purine base for use as purine nucleotide
  • especially in brain: salvage pathway enzyme
  • nucleotide required for neurotransmitter synthesis
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9
Q

Dedificiency in HGPRT: Less Nyhan syndrome

A
  • X linked
  • gout due to hyperuricemia
  • elevated PRPP exacerbated gout and promotes de novo pathway
  • serious CNS effects: mental retardation, growth retardation, choreathetosis, spasticity, self mutilation
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10
Q

Uric acid lowering therapy clinical contect

A
  • prevent acute attachs
  • eliminate tophi
  • suppress plasma urate level in context of tumor lysis syndrome
  • reverse hyperuricemia in ischemic heart disease and metabolic syndrome
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11
Q

Strategies to lower serum uric acid level

A
  • block uric acid synthesis
  • promote urinary excretion
  • convert to allantoin
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12
Q

Xanthine oxidase inhibitors lower uric acid synthesis: Allopurinol

A
  • allopurinol is a hypoxanthine analog
  • allopurinol is converted to alloxanthine by xanthine oxidase
  • alloxanthine remains bound to active site
  • xanthine oxidase undergoes suicide inhibition
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13
Q

Xanthine oxidase enzyme progile

A
  • 1330 residues protein
  • active enzyme are homodimers
  • hepatocyte cytoplasm
  • reaction centres: FeS, Mo, FAD
  • Mo cycles between +6 and +4 oxidation stated
  • alloxanthine holds Mo in +4 state -> interferes with function
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14
Q

Febuxostat

A
  • a new xanthine oxidase inhibitor
  • non-purine inhibitor
  • binds to both reduced and oxidized forms
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15
Q

Uricosirics

A
  • promote renal excretion of uric acid and block reabsorption
  • serum uric acid concentration falls
  • urinary uric acid concentration rises
  • increased risk of renal deposition and renal calculo
    Eg: probenecid, benzbromarone (effective in context of renal failure -> inhibits postsecretory tubular reabsorption)
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16
Q

Uricase

A
  • humans lack uricase
  • converts uric acid to allantoin
  • uricase is highly effective in mobilizing uric acid from tophi
  • uricase also effective in controlling uric acid levels in tumour lysis syndrome
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17
Q

Hypothesis for beneficial effects of uric acid

A
  • may be an important biological anti-oxidant

- may promote salt retention under low salt condition

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18
Q

Tumor lysis syndrome

A
  • acute elevation of plasma uric acid level

- cancer chemotherapy: increase cell death -> excess release of purine and uric acid production

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19
Q

Crystal formation

A
  • in joints, bone, skin: monosodium urate monohydrate

- in urine: uric acid crystals (because acidic environment)

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20
Q

URate crystal formation

A
  • occurs in only a minority of hyperuricemic people
  • is the critical step in the development of gout
  • is slow
  • is influenced by temperature, nucleating factors and growth inhibitors
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21
Q

Interaction between urate crystals and inflammatory system

A
  • low grade inflammation between attacks
  • rapid escalation during flares
  • spontaneous resolution without treatment
  • involves many components of the immune system
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22
Q

Early clinical features of gout

A
  • monoarticular attacks
  • rapid onset, maximal within 24 hours, severe pain
  • Pdagra or mid foot joint invovlement
  • redness and swelling around joint, heat
  • complete resolution within 7-14 days
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23
Q

Late clinical features of gout

A
  • tophi
  • oligoarticular attacks
  • involvement of knees, wrist, fingers, elbows, olecranon bursa
  • more prolonged episode with incomplete resolution
24
Q

Diagnosis of gout

A
  • confirmation is by crystal identification
  • joint aspiration and synovial fluid analysis are the best way to distinguish other forms of arthritis

CRYSTAL ARTHRITIS AND SEPSIS CAN CO-EXIST

25
Q

Monosodium urate monohydrate crystals

A
  • needle-shapred and stronly negatively bireffringent under polarised microscope
26
Q

Urate Crystal identification

A
  • almost always visible n acute gout
  • can be found in asymptomatic joint in gouty patients
  • rarely found in hyperuricemic non-gouty patients
27
Q

Beware the unexpected synovial fluid microscopy result

A
  • betamethasone crystals mimick monosodium urate crystals
  • both are strongly negatively birefringent
  • most labs will report as urate
28
Q

Serum urate and diagnosis of gout

A
  • not very useful for diagnosis
  • up to 40% of patients presenting with acute gout have serum urate lower than the limit
  • only 20% of subjects with >0.42mmol/L will develop gout
29
Q

Xrai

A
  • insensitive for gout
  • even when erosions are present, commonly mistaken for RA and vice versa
  • soft tissue swelling and cloud like calcificastion
30
Q

Ultrasound

A
  • effusion, erosion, synovitis
  • double contour sign
  • hyperechoic line over anechoic cartilage
  • layer of urate crystals on surface of cartilage
  • sensitivity 44%, specificity 99%
31
Q

Dual energy CT

A
  • high accuracy for tophaceous and well established gout
  • high sensitivity and specificity
  • uncertain accuracy in early gout
32
Q

Management of acute gout

A
  • the earlier the theraphy, the better

- choice of therapy depends on patients comorbidities

33
Q

NSAIDS

A
  • all work; choose one that the patient has tolerated previously
  • normal full dose
  • most common therapy for acute gout
34
Q

When to avoid NSAIDS in patients with gout

A
  • renal impairment
  • cardiac or liver failure
  • bleeding risk
  • peptic ulceration
  • poorly controlled hypertension
35
Q

Colchicine for acute episode

A
  • conventional dosing has very high rates of GI toxisity

- lower dose regime has much reduced toxicity but poor efficacy

36
Q

Prophylaxis and colchicine

A
  • 0.5mg twice daily
37
Q

Colchicine toxicity

A
  • Nausea, diarrhoea, vomiting
  • acute myopathy, multisystem failure
  • beware of renal failre and inhibitors of cyt P450 3A4
38
Q

Management of acure gout with intra-articular costicosteroids

A
  • Betamethasone (Celestone)
  • Methylprednisolone (DepoMedrol)
  • Triamcinolone (Kenacort)
  • can be injected after synovial fluid aspirated through same needle
  • usually requires some other therapy to prevent re-flare in following days
39
Q

Gout and corticosteroids

A
  • avoid in diabetics
  • regime can be modified depending on rapidity of response
  • if response poor, make sure there is no coexistent sepsis
  • prednisone
40
Q

Gout and tetracosactrin (ACTH)

A
  • use depot preparation
  • requires intact adrenal function
  • similar contraindications to prednisone: Diabetes
  • useful in circumstances where follw up is doubtful
41
Q

Biological therapy of gout

A
  • agents which inhibit IL1 suppress gouty inflammation

- Canakinumab: effective but extremely expensive

42
Q

ULT in gout

A
  • diagnosis should be certain or almost certail
  • never urgent
  • lifelong commitment
43
Q

Indications for ULT

A
  • tophi
  • chronic joint or tendon damage due to gout
  • multiple joint involvement
  • chronic kidney disease stage II or worse
  • history of renal calculi
  • patient choice based on frequency, severity and duration of attacks
44
Q

What questions to ask before adding urate lowering therapy in patients with gout?

A
  • can any culprit drugs be stopped

- is there another indication for one of these uricosuric: Fenofibrate and Losartan

45
Q

Dietary interventions

A
  • correction of obesity and avoidance of excess alcohol and sweetened drinks
  • dietary intervention has not been shown to be effective
46
Q

Long term management of gout

A
  • lack of compliance is the commonest cause of treatment failure
  • compliance with therapy for gout is poorer than for other chronic disorders
  • clear simple strategy is more successful
47
Q

Introduction of ULT

A
  • the faster the fall in serum concentration, the greater the risk of flare
  • prophylaxis against flares is warranted
48
Q

Urate lowering drug therapy classes

A
  • Xanthine oxidase inhibitors: Allopurinol, febuxostat
  • Uricosuric drugs: probenecid, benzbromarone, losartan, fenofibrate
  • Uricase: Rasburicase, pegloticase
49
Q

Allopurinol

A
  • xanthine oxidase inhibitor
  • renal excretion
  • reduce urate production
  • in patients with normal renal function, start at 100mg/day and increase slowly
  • a minority of patients will achieve target with 300mg/day
  • woth normal renal funciton, increasing the dose to 600mg daily will further decrease serum urate
50
Q

Severe allopurinol hypersensitivity

A
  • 1/1000
  • increased risk with renal insufficiency, increased age, thiazide use, iniital higher dose
  • starts
51
Q

Allopurino use in reanl insufficiency

A
  • start at low dose
  • warn and monitor for hypersensitivity in frist 6-12 weeks
  • progressively increase dose until maximal effect reached
  • predetermined dose based on creatinine clearance result in underdosing
52
Q

Probenecid

A
  • if allopurinol doesnt work
  • inhibits URAT1
  • increases renal urate clearance
  • good hydration, urinary alkalinisation
  • required GFR > 30-40ml.min
  • useful addition to allopurinol
  • first option for allopurinol allergic/ intolerant patients
53
Q

Febuxostat

A
  • for patietns that dont have normal renal function
  • Xanthine oxidase inhinbitor
  • rapidly orally absorbed
  • hepatic metabolism
  • no dose modification in moderate renal impairment
  • good option for allopurinol allergic/intolerant patient
54
Q

Benzbromarone

A
  • inhibits URAT1
  • increases renal urate clerance
  • good hydration/urinary alkalinisation
  • requires GFR > 20 ml/min
  • very close monitoring of LFT
  • potent uricosuric, can be added to allopurinol
55
Q

Allopurinol desensitization

A
  • dont attempt after severe reaction
  • oral dosing, increasing daily from minute amount
  • now has very little role
56
Q

Rasburicase

A
  • used to treat/prevent uric acid nephropathy in the setting of chemotherapy for sensitive bulky tumours
  • acts on both soluble urate and monosodium urate crystals, hence can produce rapid reduction in tophi
  • very short duration of action, allergy with repeated infusion and extreme expenses
57
Q

Pegloticase

A
  • uricase + polyethylene glycol
  • 8 mg ever 2 weeks
  • effective at maintaining serum urate below target
  • gout flares, infusion reaction, antipegloticase antibodies are all common
  • expensive

Block 2 - MSK (38 decks)

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