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Flashcards in GOUT - ONLINE MATERIAL Deck (57)
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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%