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Flashcards in GOUT - ONLINE MATERIAL Deck (57):
1

Origins of uric acid

- 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

2

Xanthine oxidase

- converts hypoxanthine and xanthine into uric acid
- useful therapeutic target

3

Serum urate concentraiton

- Males: 0.25 - 0.42 mM
- Females: 0.18 - 0.38mM

- solubilityof urate and crystalization are at 0.4mM

4

Uric acid levels depend on rates of

- purine nucleotide syntehsis
- purine breakdown
- purine intake
- uric acid excrtetion

5

Dietary origins of uric acid

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

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

6

Uric acid production: de Novo pathway

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

7

Salvage pathway

- divert purine base drom uric acid sunthesis and replenish nucleotide pool
- uses two enzymes: APRT and HGPRT

8

Role of salvage pathway enzymes

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

9

Dedificiency in HGPRT: Less Nyhan syndrome

- 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

10

Uric acid lowering therapy clinical contect

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

11

Strategies to lower serum uric acid level

- block uric acid synthesis
- promote urinary excretion
- convert to allantoin

12

Xanthine oxidase inhibitors lower uric acid synthesis: Allopurinol

- allopurinol is a hypoxanthine analog
- allopurinol is converted to alloxanthine by xanthine oxidase
- alloxanthine remains bound to active site
- xanthine oxidase undergoes suicide inhibition

13

Xanthine oxidase enzyme progile

- 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

14

Febuxostat

- a new xanthine oxidase inhibitor
- non-purine inhibitor
- binds to both reduced and oxidized forms

15

Uricosirics

- 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)

16

Uricase

- 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

17

Hypothesis for beneficial effects of uric acid

- may be an important biological anti-oxidant
- may promote salt retention under low salt condition

18

Tumor lysis syndrome

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

19

Crystal formation

- in joints, bone, skin: monosodium urate monohydrate
- in urine: uric acid crystals (because acidic environment)

20

URate crystal formation

- 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

21

Interaction between urate crystals and inflammatory system

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

22

Early clinical features of gout

- 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

23

Late clinical features of gout

- tophi
- oligoarticular attacks
- involvement of knees, wrist, fingers, elbows, olecranon bursa
- more prolonged episode with incomplete resolution

24

Diagnosis of gout

- 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

Monosodium urate monohydrate crystals

- needle-shapred and stronly negatively bireffringent under polarised microscope

26

Urate Crystal identification

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

27

Beware the unexpected synovial fluid microscopy result

- betamethasone crystals mimick monosodium urate crystals
- both are strongly negatively birefringent
- most labs will report as urate

28

Serum urate and diagnosis of gout

- 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

Xrai

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

30

Ultrasound

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

31

Dual energy CT

- high accuracy for tophaceous and well established gout
- high sensitivity and specificity
- uncertain accuracy in early gout

32

Management of acute gout

- the earlier the theraphy, the better
- choice of therapy depends on patients comorbidities

33

NSAIDS

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

34

When to avoid NSAIDS in patients with gout

- renal impairment
- cardiac or liver failure
- bleeding risk
- peptic ulceration
- poorly controlled hypertension

35

Colchicine for acute episode

- conventional dosing has very high rates of GI toxisity
- lower dose regime has much reduced toxicity but poor efficacy

36

Prophylaxis and colchicine

- 0.5mg twice daily

37

Colchicine toxicity

- Nausea, diarrhoea, vomiting
- acute myopathy, multisystem failure
- beware of renal failre and inhibitors of cyt P450 3A4

38

Management of acure gout with intra-articular costicosteroids

- 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

Gout and corticosteroids

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

40

Gout and tetracosactrin (ACTH)

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

41

Biological therapy of gout

- agents which inhibit IL1 suppress gouty inflammation
- Canakinumab: effective but extremely expensive

42

ULT in gout

- diagnosis should be certain or almost certail
- never urgent
- lifelong commitment

43

Indications for ULT

- 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

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

- can any culprit drugs be stopped
- is there another indication for one of these uricosuric: Fenofibrate and Losartan

45

Dietary interventions

- correction of obesity and avoidance of excess alcohol and sweetened drinks
- dietary intervention has not been shown to be effective

46

Long term management of gout

- 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

Introduction of ULT

- the faster the fall in serum concentration, the greater the risk of flare
- prophylaxis against flares is warranted

48

Urate lowering drug therapy classes

- Xanthine oxidase inhibitors: Allopurinol, febuxostat
- Uricosuric drugs: probenecid, benzbromarone, losartan, fenofibrate
- Uricase: Rasburicase, pegloticase

49

Allopurinol

- 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

Severe allopurinol hypersensitivity

- 1/1000
- increased risk with renal insufficiency, increased age, thiazide use, iniital higher dose
- starts

51

Allopurino use in reanl insufficiency

- 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

Probenecid

- 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

Febuxostat

- 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

Benzbromarone

- 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

Allopurinol desensitization

- dont attempt after severe reaction
- oral dosing, increasing daily from minute amount
- now has very little role

56

Rasburicase

- 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

Pegloticase

- 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