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3154 MSK > Gout > Flashcards

Gout Flashcards

1
Q

What is gout?

Gout syndrome can consist:

A

Disease caused by imbalance in purine metabolism and deposition of monosodium urate (MSU) crystals in articular and periarticular tissues

It is a metabolic disorder - hyperuricemia

Gout syndrome - heterogenous clinical spectrum of diseases:

  • Recurrent acute gouty arthritis (a/w urate crystals in synovial fluid)
  • Tophi (deposits of MSU crystals in tissue in and surrounding the joints)
  • Interstitial renal disease (gouty nephropathy)
  • Uric acid nephrolithiasis (uric acid kidney stones)
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2
Q

Gout incidence

A
  • More common in developed countries
  • A/w dietary and lifestyle factors linked to obesity (alcohol consumption, sugary beverages, red meat, sedentary lifestyle)
  • Male > Female (5:1, but gap narrows after menopause)
  • More common >40y

NOTE: if occur in male <30y or premenopausal women, suggests inherited enzyme defect or presence of renal disease

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3
Q

Risk factors for gout:

A
  • Obesity
  • Diet
  • Ageing (common >40y)
  • Hypertension
  • CKD
  • Diabetes
  • Hyperlipidemia
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4
Q

Explain purine metabolism pathway

A

Glutamine forms nucleic acids in body tissues

Nucleic acid is broken down into guanine and adenine => hypoxanthine => xanthine => uric acid

Purine-rich food contributes to guanine and adenine which are purine bases

Xanthine oxidase breaks down hypoxanthine to xanthine, and xanthine to uric acid

Salvage pathway: guanine and hypoxanthine can be recycled back to form nucleic acids (via HGPRT and PRPP)

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5
Q

Describe the characteristics of uric acid

  • pKa
  • Solubility
  • Excretion
A
  • Weak organic acid (pKa 5.75 in the blood)
  • Soluble in normal arterial pH of 7.4
  • Solubility limit at 6.8mg/dL - precipitates when exceeds this conc.
  • Less soluble at lower temp (e.g., at peripheral joints) => hence most common site of monosodium urate crystal deposition is the big toe and at night

Excretion:

  • 65% excreted in urine through renal tubules, reabsorbed by URAT1 and GLUT9
  • 35% in GI, degraded by intestinal flora

Note that uric acid is excreted in humans, however, in animals it is converted to Allantoin by the enzyme, uricase

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6
Q

Gout Pathophysiology:

How does inflammation occur?

A
  • Overproduction of uric acid (>600mg) - could be due to primary inborn errors of metabolism or secondary conditions that increase cell turnover and purine generation
  • Underexcretion of uric acid (<600mg/24h) - 90% of cases

=> Deposition of urate crystals in periarticular fibrous tissue of synovial joints

Main immune involvement: phagocytosis of urate crystals

  1. Hyperuricemia, ppt of urate crystals in the joints
  2. Complement activation, neutrophil chemotaxis (migration)
  3. Neutrophils phagocytose the crystals - unsuccessful, ends up causing lysing of the neutrophils and release of lysosomal enzymes that contribute to tissue injury and inflammation; crystals are then re-released, inducing phagocytosis by neutrophils once again
  4. Neutrophils also release leukotriene B4 (LTB4) as well as prostaglandins => more tissue injury and inflammation, further causes neutrophil chemotaxis => phagocytosis (positive feedback loop)

Inflammation in gout is due to leukocytes and neutrophils recognizing and attacking the urate crystals that have precipitated out of the joint, and mobilized into the blood plasma

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7
Q

Of the 3 immune cell actions, which are involved in gout?

  • Proliferation
  • Cytokine production
  • Adhesion and trafficking
A
  • Cytokine production
  • Adhesion and trafficking
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8
Q

Causes of hyperuricemia due to increased purine biosynthesis and/or urate production:

A
  1. Inherited enzyme defects leading to purine overproduction
  2. Clinical disorders leading to purine and/or urate overproduction

3. Drug and diet-induced purine and/or urate production

  • Excessive alcohol consumption
  • Excessive dietary purine ingestion
  • Excessive fructose ingestion
  • Cytotoxic drugs
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9
Q

Causes of hyperuricemia due to decreased uric acid clearance (90% of cases):

A
  1. Clinical disorders
  • Obesity
  • CKD
  • Hypertension
  • Diabetes
  • Hyperlipidemia
  1. Rare monogenic disorders causing decreased uric acid clearance
  2. Common variants in genes encoding transporters that regulate renal or gut uric acid clearance
  3. Drug and diet-induced decreased uric acid clearance
  • Diuretics (thiazide and loop, e.g., indapamide) => incr urate absorption in the renal tubules
  • Cyclosporin and tacrolimus
  • Low-dose salicylates / Aspirin => anti-uricosuric action
  • TB drugs: Ethambutol, Pyrazinamide
  • Ethanol (alcohol ca cause dehydration)
  • Nicotinic acid
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10
Q

Gout presentation

A
  1. Monoarticular at 1st MTP of great toe (usually)
  • Common sites: MCP (thumb), knee, MTP (big toe), also may occur at ankle, midfoot, wrist, elbow
  • Initially asymmetrical monoarthritis, one joint at a time
  1. Nocturnal pain
  • Typically wake up due to the excruciating pain
  • Rapid/sudden onset, overnight
  1. Severe pain for several hours (feels like joint is on fire)
  2. Joint is erythematous, hot, swollen, tender (inflammation)
  3. Swelling and discomfort continues days to weeks thereafter
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11
Q

How might gout present in advance disease (FYI)

A

Complications from gout tophi (deposits of monosodium urate crystals in soft tissues):

  • Soft tissue damage
  • Deformity
  • Joint destruction
  • Nerve compression syndrome
    etc.
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12
Q

Gout diagnosis

A

Asymptomatic hyperuricemia alone DOES NOT DIAGNOSE gout

Diagnosis is based on monosodium urate crystals in:

  1. Synovial fluid (detected in joint aspirate)
  2. OR tissue sections of tophaceous deposits (via biopsy)

Joint aspirate findings: INFLAMMATORY

  • Colour: yellow
  • Clarity: cloudy
  • Viscosity: dcr
  • WBC count: 2000-50,000 cells/mm3 (normal is <200 cells/mm3)
  • Neutrophil count: >50%
  • Gram stain: negative (not antimicrobial culture)
  • Crystals: positive for needle negative birefringent crystals

=> Presence of uric acid crystals in joint aspirate is confirmatory for gout diagnosis

Note that this requires referral to GP/polyclinic for formal diagnosis, history taking in community pharmacy is insufficient

No need referral to A&E - this is only if there are red flags like trauma, infection, malignancy

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13
Q

What further investigations may also be needed for suspected inflammatory joint effusion:

(to rule out other arthritis)

A
  • Full blood count
  • CRP
  • ESR
  • Urate
  • Antibodies (anti-CCP, RF)
  • X-ray of the joint: may reveal joint erosions/destructions
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14
Q

Gout VS Pseudogout

A

Gout: urate crystals (needle negative birefringent crystals)

Pseudogout: calcium pyrophosphate crystal deposits (rhomboid positively birefringent crystals)

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15
Q

Goals of gout treatment:

A

1. Provide rapid, safe, and effective pain relief (with anti-inflammatory during acute attacks)
2. Reduce recurrence of future attacks (via reducing serum urate concentration with ULT)
3. Address associated comorbidities or medication use
4. Prevent joint destruction and tophi formation
5. Increase quality of life

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16
Q

LIST the stages of gout:

A
  1. Asymptomatic hyperuricemia
  2. Acute gout (1st attack)
  3. Inter-critical phase (b/w flares)
  4. Chronic gout
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17
Q
  1. Asymptomatic hyperuricemia
  • Features
  • Pharmacotherapy
A

Features:

  • Male: plasma uric acid >7mg/dL (450umol/L) [210-420]
  • Female: plasma uric acid >6mg/dL (360umol/L) [150-350]

Pharmacotherapy:

  • None (NTT is high to prevent 1 incident)
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18
Q
  1. Acute gout (1st attack)
  • Features
  • Pharmacotherapy
A

Features:

  • Acute arthritis
  • Typically 1st MTP
  • Excruciating pain

Pharmacotherapy:

  • 1st line: Colchicine
  • Alternatives: NSAIDs, Corticosteroids - Prednisolone
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19
Q
  1. Intercritical phase (b/w flares)
  • Features
  • Pharmacotherapy
A

Features:

  • Asymptomatic hyperuricemia (symptom-free)
  • 10% may never have another gout attack

Pharmacotherapy:

  • None
20
Q
  1. Chronic gout
  • Features
  • Pharmacotherapy
A

Features

  • Hyperuricemia
  • Development of tophi
  • Recurrent attack of acute gout (frequent attacked)

Pharmacotherapy: Urate-lowering therapy (ULT)

  • 1st line: Xanthine Oxidase inhibitors (Allopurinol, Febuxostat)
  • 2nd line: Uricosuric agents (Probenecid)
21
Q

[Management of Acute Flares]

When and what to initiate? (include dosing)

Comment on dosing in renal impairment

A

Initiate Colchicine soonest possible (within 24h)

Recall less effective if started >36h after pain onset

Low-dose colchicine regimens are used for acute flare treatment:

  • One-off treatment with 1mg LD, followed by 0.5mg 1h later

OR

  • 0.5mg BD/TDS until the acute flare resolves

Note: max dose per day is 1.5mg; doses greater than ceiling dose of 1.5mg/d may increase likelihood of GI SEs (N/V/D) with no added benefits)

Renal impairment: (unsure about hepatic)

  • Consider reducing colchicine dose or increasing dosing interval
22
Q

[Management of Acute Flares]

Oral NSAIDs/Coxibs

  • Dosing of Celecoxib
  • When to initiate
  • Duration, when to discontinue
  • Renal impairment
A

E.g., Celecoxib

  • Initial 400mg, followed by 200mg approximately 12h later on day one; continue 200mg BD thereafter (max dose: 400mg/day)
  • Begin within 24-48h of flare onset
  • Discontinue 2-3 days after resolution of clinical signs
  • Usual duration: 5-7 days
  • Consider adding PPI
  • Renal impairment: not suitable for patients with CrCl <30ml/min or for prolonged duration (not for prophylaxis use)
23
Q

[Management of Acute Flares]

Oral corticosteroids

  • Dose
  • Duration
  • Discontinuation
  • Renal impairment
A

Short course of Prednisolone

  • 30-40mg/day given once daily or in two divided doses until symptom improvement; if weight based: 0.5mg/kg/day
  • Usual duration at the above dosing: 2-5 days
  • Then, taper gradually (half-dose) as tolerated over the next 7-10 days
  • Renal impairment: Prednisolone may be better choice over Colchicine and NSAIDs
24
Q

[Management of Acute Flares]

Intraarticular corticosteroids

  • Considerations for use
A

Only considered if patient cannot take PO meds

ACR/NICE: IM glucocorticosteroids can be considered as well

25
Q

[Management of Acute Flares]

Given NSAIDs, colchicine, and corticosteroids are unsuitable/ineffective, what might be done?

A

Refer to rheumatology, may prescribe IL-1 inhibitor

26
Q

[Management of Acute Flares]

Non-pharmacological adjuvant:

A

Topical ice + rest affected joint

  • cold therapy to alleviate pain
27
Q

[Management of Acute Flares]

Follow-up appointment after gout flare should assess:

A
  • Measure serum urate levels
  • Provide information
  • Assess lifestyle and comorbidities (healthy balanced diet, manage body weight, exercise, reduce alcohol consumption)
  • Review meds, discuss risk and benefits of long term ULT to eliminate urate crystals, prevent flares, shrink tophi, and prevent long-term joint damage

Advise that excess body weight and excessive alcohol can exacerbate gout flares and symptoms

28
Q

[Prophylaxis against Acute Flares during ULT initiation]

  • Indication
  • Options + Doses
  • Duration
A

Indication

  • Purpose on anti-inflammatory is to prevent acute flare while on ULT, while target serum urate level is being reached
  • Meaning restart anti-inflammatory together with initiation of ULT 2-4 weeks after the flare

Anti-inflammatory options:

  • Colchicine 0.5mg OD
  • Low dose oral NSAID/Coxib - e.g., Celecoxib 200mg OD
  • Low-dose oral corticosteroid - e.g., Prednisolone 5-7.5mg OD

Duration: 3 to 6 months

  • ACR: shorter durations a/w flares upon cessation of prophylaxis
29
Q

[Prophylaxis against Acute Flares during ULT initiation]

What if an acute flare happens during prophylaxis?

A

Use the higher acute flare treatment dose instead of the prophylactic dose

Reinitiate prophylactic dose after acute flare resolves

If a diff med is used to treat the acute flare, exercise caution with combi of oral NSAID + oral prednisolone (incr risk of GI ulcer and bleed)

30
Q

[Initiation of Urate Lowering Therapy]

ULT: Treat-to-target therapy

  • What are the serum urate level targets?
  • How to treat to target?
A

Targets:

Non-tophaceous gout: <360umol/L (6mg/dL)

Tophaceous gout: <300umol/L (5mg/dL)

  • Tophi
  • Chronic gouty arthritis
  • Ongoing frequent flares despite serum urate level <360umol/L (6mg/dL)

Treat-to-target:

  • Start with low-dose ULT
  • Monthly monitoring of urate serum levels to guide dose increases, as tolerated, until target serum urate level reached
31
Q

[Initiation of Urate Lowering Therapy]

Considerations to initiate ULT

A

NICE 2022:

  • Multiple or troublesome flares (>=2 per year)
  • Tophi
  • Chronic gouty arthritis (hyperuricemia, tophi, recurrent gout attacks)
  • CKD Stages 3-5 (GFR <60ml/min/1.73m2)
  • Diuretic therapy

ACE 2019:

  • Frequent acute gout flares (>=2 per year)
  • Tophi
  • Clinical or imaging findings of gouty arthropathy
  • History of urolithiasis (kidney stones)

ACR 2020:

  • Frequent acute gout flares (>=2 per year)
  • Tophi
  • Radiographic damage attribution to gout

NOT recommended to start ULT for stage 1 and 3:

  1. Asymptomatic hyperuricemia - pt with hyperuricemia with no prior gout flares or tophi
  2. Intercritical phase b/w flares - pt experiencing first flare
32
Q

[Initiation of Urate Lowering Therapy]

When to initiate ULT

A

Recommended: Initiate at least 2-4 weeks after a gout flare has settled

However, may initiate during a flare without waiting for it to be resolved if:

  • Flares are more frequent
  • Very high serum urate level that we want to bring down
  • Reduce risk of pt not returning for ULT treatment 2-4 weeks later
  • Pt may be highly motivated for tx due to symptoms related to current flare

Starting ULT during a flare DOES NOT significantly extend flare duration or severity

33
Q

[Initiation of Urate Lowering Therapy]

Why is it recommended to start ULT 2-4 weeks after gout flare has resolved?

A

ULT may precipitate acute flares during initial period of ULT

During acute attack, there is mobilization of uric acid out of joints into the blood

ULT lowers plasma uric acid concentrations, this can increase the gradient of uric acid from joint to plasma, causing increase mobilization of uric crystals out of joints into the plasma

Immune cells in the blood recognize and attack the urate crystals in the plasma, causing inflammation, thereby worsening the acute gout attack

Moreover, for probenecid, there may be increased risk for uric kidney stone formation, as kidneys unable to handle the increased amount of uric acid to be excreted during an acute flare

34
Q

[Initiation of Urate Lowering Therapy]

Dosing of Allopurinol (1st line, subsidized)

A

Dosing range: 100-800mg/day

Initiation: =<100mg/day

Initiation in CKD stage 3 and above (<60ml/min/1.73m2): =<50mg/day

Titration: 50-100mg increments q2-8 weeks (treat-to-target, monitor serum urate levels, clinical response, and SEs)

Usual maintenance: >300mg/day (acceptable for renal impairment)

Max dose: 800-900mg;/day (in normal renal function only)

Lower dose is used in renal impairment because Allopurinol is cleared by the kidneys

35
Q

[Initiation of Urate Lowering Therapy]

Dosing of Febuxostat (1st line, more ex, may use in pt intolerant to Allopurinol)

A

Dosing range: 40mg or 80mg OD

Initiation: =<40mg/day

Titration: 80mg/day if treatment target not met after 2-4 weeks

Metabolized by the liver, hence no adjustment with renal impairment

36
Q

[Initiation of Urate Lowering Therapy]

Dosing of Probenecid (2nd line)

A

Dosing range: 500-3000mg/day

Initiation: 250mg BD x 1w, then 500mg BD

Titration: increase by 500mg q4w as tolerated if symptoms are not controlled

Usual maintenance: =<2000mg/day

Renal impairment: (due to it’s MOA)

  • Not recommended in pt with CrCl <50ml/min
  • Not effective in pt with CKD

Note: take plenty of fluid (>=2L of water) to prevent kidney stones (urolithiasis) from forming; CI in pt with hx of urolithiasis

37
Q

ULT treatment duration

Clinical remission definition

A

Clinical remission = no flares for >= 1 year and no tophi

If therapy is well-tolerated and not burdensome, patient can have preference to continue or stop treatment => SDM

Most patient may wish to continue due to concerns about return or worsening of gout symptoms, tophi, or joint damage if ULT is stopped

Educate patient:

  • high levels of urate in blood can form new urate crystals
  • gout is a lifelong condition that will benefit from long-term ULT
  • usually, tx is continued after target serum urate levels is reached, with annual monitoring (NICE)
38
Q

What should be done if patient is already on ULT and has an acute flare?

A
  • Continue ULT during the flare
  • Consider increasing colchicine to treat the flare, or add NSAID/Prednisolone
  • If on prophylactic dose of anti-inflammatory, should increase to higher acute flare treatment dose
39
Q

When should rheumatology referral be considered?

A

[NICE]

  • Diagnosis of gout is uncertain
  • Treatment is contraindicated, not tolerated, or ineffective (may need use IL-1 inhibitor for acute flare)
  • CKD stages 3b-5 (<45ml/min/1.73m2)
  • they have had an organ transplant

[ACE]

  • Severe or refractory gout
  • Severe renal impairment
  • Difficulty achieving management goal, particularly with renal impairment
  • Serious adverse effects from ULT
40
Q

[Non-pharmacological for Gout]

To alleviate pain in acute flare:

A

Topical ice (cold therapy) + rest affected joint

41
Q

[Non-pharmacological for Gout]

To reduce risk for flares:

A
  • Limit alcohol intake (mechanism: alcohol dcr uric acid excretion in urine, cause dehydration cause uric acid to ppt etc.)
  • Limit purine-rich food (e.g., red meat, anchovies, peanuts, durian, organ meat - liver, asparagus, cauliflower, mushroom, seafood, beer, nuts, beans)
  • Limit high-fructose corn syrup (e.g., beverages)
  • Weight management, a/w obesity
42
Q

[Non-pharmacological for Gout]

Patient education:

A
  1. Healthy lifestyle
  • healthy diet
  • healthy weight
  • exercise
  • avoid smoking
  1. Avoid
  • excessive alcohol
  • sugary drinks (obesity, fructose)
  • excessive purine-rich foods
  1. Include more
  • low-fat dairy products
  • vegetables
  • fluids (at least 2L - esp impt if on probenecid)
43
Q

[Non-pharmacological for Gout]

Exercise

A

After a gout flare subsides,

  • May start with some low-impact aerobic exercises such as walking or swimming, riding a stationary bicycle
  • It is important to keep joints flexible by incorporating stretching and range-of-motion exercises as well (e.g., slowly moving forward and backward, then rotate – repeat 5 times and gradually increase repetitions)
  • Afterwards, strengthening exercises would be important to build muscle so that you can protect your joint, try simple resistance training using an elastic resistance band (Strength training has been shown to be helpful in managing other conditions such as osteoarthritis and rheumatoid arthritis, but little research has been done regarding strength training and gout. Nevertheless, lower extremity strength often decreases in those managing gout. Therefore, strength training especially for the lower extremities can be helpful to add to your exercise plan )
44
Q

[Med Review of existing meds: conditional recommendations]

Hydrochlorothiazide

A

Conditional Recommendation: Switch hydrochlorothiazide to alternative antihypertensive

  • Hydrochlorothiazide decreases urate excretion (reabsorb uric acid)
  • Thiazide diuretics also increase hypersensitivity reaction/toxicity of allopurinol
45
Q

[Med Review of existing meds: conditional recommendations]

Antihypertensive choice

A

Conditional recommendation: Use Losartan preferentially as antihypertensive

  • ACEi and ARB have uricosuric effect
  • However, ACEi may increase hypersensitivity reaction/toxicity of allopurinol
46
Q

[Med Review of existing meds: conditional recommendations]

Low-dose aspirin

A

DO NOT STOP low-dose aspirin if indicated

  • Even though low-dose aspirin has anti-uricosuric action (incr urate reabsorption)
  • If indicated (e.g., AMI, AIS) - monitor, counsel on non-pharm strategies to reduce urate levels
47
Q

[Med Review of existing meds: conditional recommendations]

Cholesterol-lowering agents

A

DO NOT add/switch cholesterol-lowering agents to fenofibrate

  • Even though fenofibrate has uricosuric action and can increase uric acid excretion by inhibiting URAT1 and SLC22A12

3154 MSK (12 decks)

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