gout Flashcards
gout definition
Imbalance in purine metabolism (production > excretion)
Deposits of monosodium urate (MSU) crystals in articular & periarticular tissues
* Leads to inflamm: pain & swelling
gout syndrome
- Recurrent acute gouty arthritis
○ Assoc w/ urate crystals in synovial fluid - Tophi
○ Deposits of MSU crystals in tissue & surrounding joint - Interstitial renal disease
○ Gouty nephropathy - Uric acid nephrolithiasis
○ Uric acid kidney stones
risk factors
- dietary and lifestyle factors
- obese pts
Asx hyperuricemia (uric acid) assoc w/ HTN, CKD, insulin resistant, CVD
purine metabolism
- Glutamine + PRPP –> nucleic acids in body tissues (RNA, DNA)
- Break down —> Guanine & Adenine
○ Recycled to form nucleic acids (HGPRT + PRPP) - Break down —> hypoxanthine
○ Recycled to form nucleic acids - XANTHINE (XO)
- URIC ACID (XO)
uric acid properties
○ Weak organic acid (Pka 5.75 in blood)
○ Soluble in normal arterial pH of 7.4
○ Solubility limit at 6.8mg/dL
○ Less soluble at lower temp = Peripheral joints
uric acid animal vs human
- Excreted in humans
○ 65% in urine (reabsorbed by urate transporter 1, URAT1 & GLUT9)
○ 35% in GI (degrade by intestinal flora) - animals (uric acid –> allantoin) by uricase
gout patho
- High uric acids –> crystallised and hidden in joints
- TRAUMA Releases crystals into blood plasma
- Immune cells activated, recognise and attack crystals
○ Proliferation of immune cells (neutrophils, macrophage)
○ Cytokine production
○ Adhesion and trafficking - Inflammation as leukocytes attack urate crystals
+ve feedback that incr inflammation
- Incr inflammation as neutrophils try unsuccessfully to phagocytize urate crystals
○ Crystals lyse neutrophils (released out)
○ Release lysosomal enzymes too
○ More damage to joint & tissues
+ve feedback loop
2 main pathways
1) Over production of uric acids (excrete > 600mg)
2) Underexcretion of uric acid (<600mg/24h)
Incr uric acid > solubility = deposition of urate crystals
- Periarticular fibrous tissue of synovial joints
- Renal tubules
overprod
> 600mg excrete
* PRIMARY: inborn error in metabolism
* Secondary: conditions that incr cell turnover & purine generation
* Diet (purine rich foods)
* Incr Guanine & Adenine
underexcretion
<600mg excrete
* Incr uric acid conc (reabsorbed by urate transporter 1, URAT1 & GLUT9)
* 90% of gout cases
measure uric acid excretion
not commonly done as diet is difficult
- Serum uric acid & 24h urine
- purine free diet
> 600mg excrete: OVER-production
<600mg excrete: UNDER-excretion
gout presentation
- Usually monoarticular (MTP of great toe)
- Most common at periphery (lower temp = incr ppt)
- Occur one joint at a time
- Sleep disrupted by pain
- Severe pain x hrs
- Pain resolves but swelling and discomfort continues days~wks
- Joint red, hot, swollen, tender
- Chronic gout
- Tophaceous/ tophi formation
○ Pus (urate crystals + inflamm cells, no microog) - Joint damage
- Tophaceous/ tophi formation
dx of gout
Monosodium urate crystals Microscopy (birefringent 2 sharp points)
* Synovial fluid (joint aspirate)
* May look diff: turbid, pus (infection), blood
* Yellow, cloudy, low viscosity
* High WBC, neut
* -ve microbial (not septic)
* Tophaceous deposits (tissue secretions)
Asx hyperURICemia =/= gout
hyperuricemia levels
- W: > 6mg/dL (450umol/L)
- M: > 7 mg/dL (360umol/L)
stages of gout
- Asx hyperuricemia = no tx
- Acute attack = colchicine, NSAID, CS
- Acute arthritis
- 1st MTP
- Excruciating pain
- Intercritical phase = no tx (10% not have another acute attack)
- Chronic gout = ULT
- Clinical or imaging findings of gouty arthropathy damage
- Hx of urolithiasis (kidney stone)
- Tophi formation
- freq acute gout attack (≥2/yr)
Consider: diuretic therapy, CKD stage 3-5
goals of gout tx
- Provide rapid, safe, effective pain relief
- Reduce future attacks
- Reduce SU conc (taken at baseline + monitored)
- Treat to target conc
- Address assoc comorbidities (kidney, medication use)
- Prevent complications
- joint destruction and tophi formation
- Incr QOL
- joint destruction and tophi formation
tx acute inflamm
- Colchicine
○ Reduce leukocyte migration into joints - Non-selective NSAIDs (naproxen, indomethacin)
○ Anti-inflamm and analgesic
Indomethacin: older NSAID (wider MOA = inhibit phospholipase A2 + COX) - COX2 selective NSAIDs (celecoxib)
- Glucocorticoids (prednisolone PO or intra-articular inj)
consideration of acute gout tx
- Combi therapy (reduce inflamm asap)
- Colchicine + NSAID/ COXIBS
- Colchicine + prednisolone
- X NSAID + CS
- Non-pharm: topical ice
- Start ULT (if indicated)
- 2-4wks later after acute, sx resolved
- Start even when on flare if
* Pt non-adherence, not return
*Pt highly motivated for tx
chronic gout prevention tx
- Xanthine oxidase inhibitors [allopurinol, febuxostat]
○ Decr production of uric acid
○ Incr migration of crystals from joint to plasma - Uricosuric agents [Probenecid]
○ Incr excretion of urate through kidneys
○ Push uric acids from blood to kidney - incr uric acid metabolism [pegioticase]
○ recombinant PEGylated uricase, incr uric acid metabolism
monitor
- SU level (tx to target: base, mnthly – until reach target)
- Annual if continue tx
○ Non-tophaceous: <360umol/L (6mg/dL)
○ Tophaceous: <300umol/L (5mg/dL) - Assess lifestyle and comorbidities
○ Obesity, HTN, CKD - Review meds (int?)
- Non-pharm
○ Diet, weight, alcohol - Need for ULT? (freq attack)
ULT duration
- Clinical remission = no flares ≥ 1 yr + no tophi
○ Low SU < 7mg/dL - If discontinue + higher SU ==> more freq flares (worsening/ return of gout sx, tophi, joint damage)
- Therapy well-tolerated, not burdensome: pt can continue/ stop
celecoxib dose acute & prophylaxis
acute: 400mg LD -> 200mg
200mg BD (5-7d, until sx resolve)
Prophylaxis: 200mg OD
CS prednisolone dose acute & prophylaxis
acute: 30-40mg OD (or divide to 2 dose), 2-5d until sx resolve
* Taper by half dose over 7d (discontinue)
* (weight) 0.5mg/kg OD 2-5 d –> taper
Prophylaxis: 5-7.5mg OD
colchicine used within
○ Reduce leukocyte migration into joints
○ Only use at start of gouty attack (24-36hr)
○ Phagocytosis, feedback loop would have started (cytokines released alr)
○ ceiling effect (high dose leads to SE)
colchicine MOA
- Binds to tubulin
- Prevent tubulin polymerisation into microtubules
- Inhibit leukocyte migration and phagocytosis
- Inhibits leukotriene B4 (LTB4) and prostaglandin (PG) production (pain sensitisation)
Relieve pain and inflammation in acute gouty attack within 24-36hrs
colchicine SE
- Inhibit microtubule polymerisation, at high conc inhibits cell proliferation. - Affects rapidly multiplying cells (GI epithelial cells, hair, growth factors)
- Hair loss
- GIT: NVD, abdominal pain
- Muscle weakness
- Unusual bleeding, pale lips, change in urine amt.
coclchicine dose (acute flares)
max 1.5mg/day
* 1mg LD –> 0.5 mg 1hr later
* OR 0.5mg BD-TDS
colchicine prophylaxis dose
adjunct with ULT:
0.5mg OD/ BD (max 1.2mg/day)
If flare up occurs: incr dose to acute flare dose
DDI colchicine
CYP3A4i: Macrolide, azoles, statins, verapamil, diltiazem
Grapefruit juice
CYP3A4inducers: PT, CBT, st john’s wort, rifampicin
colchicine CI/ caution
Renal (< 30ml/min)
Hepatic impairment (severe)
- Incr risk of toxicity (myopathy, neuropathy, pancytopenia)
XOi used when
Not in acute attacks:
○ Lowers plasma uric acid conc
○ Incr migration of crystals from joint to plasma
○ Attacked by immune cells. Exacerbates inflammation
allopurinol/ febuxostat MOA
- Anti-hyperuricemic agents
- Allopurinol: analogue of xanthine
- Febuxostat: competitive inhibitor of xanthine oxidase
(hypoxanthine –> xanthine –> uric acid)
- Decr uric acid production
- <6.0mg/dL
indication of XOi
- Debilitating gout attacks
- Chronic erosive arthritis
- Urate nephrolithiasis (kidney stones)
XOi ADR
Skin rash, NVD, fever, sore throat, stomach pain, dark urine, jaundice
allopurinol vs febuxostat
allopurinol
* (1st line, cheap $0.10/tab)
* renal metabolism
* higher risk of SCAR
febuxostat
* (if cannot tolerate, $3.90/tab)
* liver metabolism
* caution: HF, CHD
* lower risk of SCAR
allopurinol dose
- Initiate: ≤100mg/day
- CKD stage ≥3, <50ml/min: ≤50mg/day
- Titrate: 50-100mg incr every 2-8wks
- Monitor SU, clinical resp (dose adj to target), drug toxicity SCAR
- maintain: > 300mg/day
Max 800-900mg/day (normal RF)
100-800mg/day
febuxostat dose
40-80mg OD
Initiate: ≤40mg/day
Titrate: 80mg/day
If target not met after 2-4 wks
febuxostat CI
Liver metabolism
Risk of SCAR (< allopurinol)
Caution: HF, CHD
caution of XOi (allopurinol mainly)
- Allopurinol hypersensitive syndrome (AHS)
- Severe cutaneous adr (SCAR)
incr SCAR RISK:
○ Renal impaired (CrCL < 60ml/min)
○ Thiazide therapy
○ HLA-B*58:01 genotype (chinese, thai, korean)
SCAR presentation
SCAR within first 3mnths (but monitor throughout)
SJS, TEN: Fever + mucocutaneous lesions –> necrosis, slough of epidermis
DRESS: Rash + fever + multiorgan failure (Liver, kid, heart, lungs)
PGx of allopurinol
- HLAA-B*5801 allele
- More common in Asians (Han Chinese, Thai), Black, Native
- Testing more useful in pts alr at higher risk of allopurinol-induced SCAR
- Renal impairment
- Older age
- just counsel for ULT (allopurinol & febuxostat)
- monitor initial 3 mnths (after that too)
why testing not routine
- Rarity of allopurinol-induced SCAR (3 in 1,000) pts may develop SCAR
- Low PPV (2 in 1000) pts that test +ve actually develop SCAR
- Lack of alternative cost-effective ULT options
- Reaction can happen w/o the allele due to non-genetic factors
DDI with allopurinol
incr bone marrow sup
6-mercaptopurine
azathioprine
cyclophosphamide
DDI with allopurinol
monitor tx as incr conc of ___
CBP
warfarin
theophylline
pegloticase
DDI with allopurinol
incr hypersensitivity rxn
ACEi
loop diuretics
thiazide
ampicillin/ amoxicillin
probenecid used when
- Not in acute attacks
- Push uric acids from blood to kidney
- Risk kidney stones formation when uric acid conc too high
- When allopurinol CI in tophaceous gout (sustained high lvl of uric acids)
- Incrly freq gout attack
2-3wk after acute attack
probenecid MOA
URAT1 & GLUT9 inhibitor
decr uric acid reabsorption, increase excretion
probenecid dose
- Initiate: 250mg BD 1wk –> 500mg BD
- Titrate: 500mg every 4wks
- As tolerates, to reach target
- Maintain: ≤2g/day
500-3000mg/ day
probenecid caution
- Plenty of fluids to minimise renal stone formation (>2L/day)
- Keep urine pH > 6
- Admin alkaline (K citrate)
- Less renal stones formed
probenecid adr
NV, painful urination, lower back pain, allergic rxn, rash
probenecid CI/ caution
Not recom: crcl <50ml/min
G6PD def (Risk of haemolytic anemia)
CI: urolithiasis , CKD
non-pharm
- healthy lifestyle
* weight (obesity)
* exercise
* avoid smoke, alcohol intake
* diet (high purine: seafood, red meat, peanuts, high fructose)
med review
- ALT antihypertensives (maybe ACEi, ARB - uricosuric effect)
* Hydrochlorothiazide decr urate excretion
* ACEi DDI w/ allopurinol - Do not stop low-dose aspirin (CVS prophylaxis)
* Despite incr urate reabsorption - Do not ADD/ SWITCH antihyperlipidemic meds
* Esp fenofibrate despite uricosuric effects
