Week 3- Gout

Question 1

what is gout?

Answer 1

its a group of diseases of increased levels of uric acid in the blood- HYPERURICAEMIA

Question 2

what is gout caused by?

Answer 2

increase production or decreased excretion or both

Question 3

what is happeneing during gout?

Answer 3

• Deposition of monosodium urate
  monohydrate crystals in joints & soft tissues
  ➔ acute inflammation & eventually tissue damage

Question 4

what is the epidemilogy of gout?

Answer 4

• more common in men 30-60yrs and in older ppl

- more likely if there is family history of it

Question 5

what is the physiology of gout?

Answer 5

-normally for synthesis Uric acid is end product of purine (adenine & guanine) metabolism.
-last 2 steps controlled by xanthine oxidase
-nomrally for uric acid excertion
- Completely filtered by glomerulus
-90-100% reabsorbed in proximal tubule
(URAT-1 specific anion transporter)
-50% actively secreted in distal tubule
-40-45% post secretary reabsorption
➔ ~ 5-10% of original glomerular load is
excreted

Question 6

what is the aetiology of gout?

Answer 6

-icnreased rate of synthesis of purine precursors of
uric acid (10%)
- decreased elimination of uric acid by kidney (90%)

Question 7

what are the 2 types of gout?

Answer 7

-Primary:
– Due to rare inborn errors of metabolism or renal
excretion (not covered here)
- Secondary:
– Occur due to drugs or consequence of other
disorder

Question 8

what is the explantation of gout due to over consumption of uric aicd?

Answer 8

-Offal (liver, kidney, heart, sweetbreads), game,
oily fish (anchovies, herring, mackerel, sardines,
sprats, trout), seafood, yeast or meat extracts.

Question 9

what is the explantation of gout due to over production of uric acid?

Answer 9

⚫ Excessive cell turnover (E.g: neoplastic
disease, psoriasis, haemolytic anaemias)
⚫ Cell lysis caused by cancer chemotherapy &
radiotherapy
⚫ Excessive synthesis of uric acid due to rare
enzyme mutation defects

Question 10

what is the explantation of gout due to under excretion of uric acid?

Answer 10

Hyperuricaemia ➔ large urate loads filtered
through glomerulus ➔ increased urate reabsorption
to avoid dumping of insoluble urate into
urinary tract
-Also reduction tubular secretion

Question 11

what type of situation would you get under excretion of uric acid?

Answer 11

-renal failure, kidney cant excrete it
-alcohol (beer, red wine) have high levels of purine, when its breaks down produced uric acid and excretion in kidney
-Drugs:
– Diuretics - Especially thiazides, furosemide
– aspirin, ciclosporin,, omeprazole, ethambutol,
pyrazinamide, niacin, didanosine, levodopa,
cytotoxics

Question 12

what are other causes for gout and risk factors?

Answer 12

⚫ Physical Stress
– Tight shoes, hill walking, hiking, history of joint
trauma
⚫ Other independent risk factors: hypertension,
obesity & hypertriglyceridaemia

Question 13

what is the gout pathophysiology?

Answer 13

– Formation and deposition of monosodium urate crystals is more likely to occur when levels
are persistently > 380 micromol/mL (solubility limit)
⚫ HIGHER plasma urate level ➔ increased incidence of gout
⚫ PROLONGED DURATION of increase urate levels ➔ increased likelihood of developing gout.

Question 14

when is uric acid a probelm?

Answer 14

-when its supersaturation withn join and formation crystals
-Solubility is influenced by:
– Temperature, pH, cation concentration, articular
dehydration and presence of nucleating agents (nonaggregated proteoglycans, insoluble collagens and
chondroitin)

Question 15

when may a patient have symptoms of gout?

Answer 15

-crystal are shed in the bursa triggering inflammatory reaction (small sacs of synovial fluid surrounding
joint)
-Crystal deposition may continue for many
months or years without causing symptoms

Question 16

what are some symptoms that a patient might experience?

Answer 16

Shedding can be triggered by e.g:
– Trauma, dehydration, rapid weight loss, illness &
surgery

Question 17

what do the urate crystals do once they are in the bursa?

Answer 17

Urate crystals are directly able to initiate, amplify
and sustain inflammatory responses, through:
⚫ Humoral and cellular inflammatory mediators
⚫ Complement system
⚫ Overall this causes:
⚫ a proinflammatory cascade of cytokines, chemotactic factors,
TNF
⚫ Inflammatory cell accumulation (monocytes and mast cells in
the early phase and neutrophils in the later phase)
⚫ IL-1beta has been shown to be critically related to
the inflammatory response in gout

Question 18

what are the 5 stages clinical presentation of gout?

Answer 18

– Asymptomatic hyperuricaemia (long period before gout manifests)
– Acute gouty arthritis
– Interval gout/Intercritical gout
– Chronic tophaceous gout
– Gouty nephropathy

Question 19

what is acute gouty arthritis?

Answer 19

-first acute attack of gout, 90% monoarticular
⚫ 80% first metatarsophalangeal joint of great
toe (podagra)
⚫ Others: small joints of feet/ankles, hands
(distal interphalangeal), elbows & knees
⚫ Caused by deposition of urate crystals in
joints

Question 20

what are some signs and symptoms of gout?

Answer 20

⚫ Severe pain with hot, red, swollen and
extremely painful joints
⚫ Begin abruptly – max intensity 8-12hrs
⚫ Weight bearing impossible
⚫ Erythema(redness)
⚫ Synovitis(inflammation)
⚫ Leucocytosis(increase in wbc)
⚫ Confusion in elderly

Question 21

when do attacks of gout happen?

Answer 21

⚫ Attack at anytime but can be caused by
trigger factors (E.g: food, alcohol,
dehydration, starting diuretic)
⚫ Left untreated last around 7 days ➔
desquamation(shredding of outer layer of skin) of overlying skin

Question 22

what is intercritical gout?

Answer 22

⚫ Time between acute attacks of gout
⚫ Variable intervals of months to years when
there are no symptoms

Question 23

what is chronic tophaceous gout?

Answer 23

⚫ Presence of tophi:
– White deposits of monosodium urate
– Nodule formation affecting joints
– Subcutaneous and periarticular areas
– Ear lobes, Achilles tendon, fingers
-paitent who have this had probs had gout for 10-15 years

Question 24

what is Gouty nephropathy/ Hyperuricaemia

induced renal disease?

Answer 24

⚫ Crystals of urate deposited around renal
tubules
➔ inflammatory response (interstitial
nephritis)
⚫ Proteinuria & renal impairment
⚫ Renal stone formation

Question 25

how is gout diagnosed?

Answer 25

⚫ Has to be based on clinical history and examination.
⚫ Uric acid levels can be useful but are not always
raised when someone has an acute attack.
⚫ Joint fluid microscopy – presence of crystals and
absence of infection (to rule out septic arthritis)
– Not always done as it risks causing infection
⚫ Joint X-ray
⚫ Standard bloods – RF, lipids, glucose

Question 26

what are the aims for the treatment of gout?

Answer 26

⚫ Relieve pain/inflammation of acute attack
⚫ Terminate attack
⚫ Prevent further attacks
⚫ Prevent long term joint and organ damage
⚫ Avoid precipitating factors

Question 27

what should a patient do if they get an acute attack?

Answer 27

-rest
-prompt treatment with full dose NSAIDs
-avoid ASPIRIN, – Competes with uric acid for excretion and can
worsen attack

Question 28

what is the first line treatment for gout?

Answer 28

-first line is NSAID relieve pain and inflammation and can abort an acute attack. if fast
-should be started ASAP
-Full therapeutic high dose for 24-48hrs then
lower doses for 7-10 days until completely
resolved
⚫ Consider gastroprotection (ppi) e.g. lansoprazole

Question 29

what is the second line treatment for gout?

Answer 29

COLCHICINE- when NSAID are ineffective or contraindicted in CV, heart failure or HT, renal disease, gastrointestinal
-works by Slower onset + high level of toxicity
⚫ Inhibits neutrophil migration into joint
-⚫ Dose: 0.5mg 2-4 times a day until relief of
joint pain or development of GI side-effects
or total 6mg taken – do not repeat course
within 3 days
⚫ Lower dose of 0.5mg every 8 hrs in elderly
and renal impairment
-Response after 6 hrs, pain relief after 12 hrs
and resolution after 48-72 hrs

Question 30

what are some interaction for colchicine?

Answer 30

-glycoprotein inhibitor

Question 31

what are some side effects of colchicine?

Answer 31

– Nausea & vomiting
– Abdominal pain
– Diarrhoea (stop therapy immediately)
– Rashes, peripheral neuropathy, blood dyscrasias these are rare

Question 32

what is other treatment for gout

Answer 32

⚫ Oral: e.g. Prednisolone 30-35mg daily (or
equivalent)
-Pred 35mg daily for 5 days as effective as naproxen
500mg BD for 5 days for flare treatment
-Pred 30mg daily for 5 days has analgesic effectiveness
equivalent to indomethacin
⚫ Articular: e.g. Triamcinolone = good safety
profile
– Consider particularly in monoarthritis of easily
accessible joint

Question 33

what is combination therapy for got?

Answer 33

NSAID with colchicine or corticosteroid

Question 34

how does prophylaxis(Urate Lowering Therapy – ULT) help gut?

Answer 34

helps prevent long term complications
-should be considered when patient suffers two or more acute attacks per year, ), tophi, chronic
gouty arthritis, joint damage, renal
impairment, urolithiasis, diuretic use, young

Question 35

why dont you start prophylaxis during an acute attack?

Answer 35

⚫ Hyperuricaemic for several years ➔ no need
to treat hyperuricaemia immediately
⚫ Changes (decrease ) serum uric acid levels ➔
mobilisation of uric acid stores ➔ may
prolong attack or precipitate another

Question 36

what does Urate Lowering TherapY do?

Answer 36

– Reduces frequency of flare
– Once crystals dissolved avoids recurrence
– Reduces size and number of tophi
– Facilitates tophi disappearance
⚫ IMPROVED QoL

Question 37

when is colchicine used as first line?

Answer 37

-when using prophylaxis AT A DOSE OF 0.5-1mg daily

if CI use low NSAIDS AND ppi

Question 38

What is used first line for ULR?

Answer 38

allopurinol
⚫ Controls symptoms
⚫ Some improvement in tophi (usually after
about 6 months treatment)

Question 39

what is the mechanism of action for allopurional?

Answer 39

⚫ Xanthine oxidase inhibitor
⚫ Pro-drug ➔ undergoes hepatic metabolism
to active metabolite, oxipurinol

Question 40

what dose of allopurinol is used?

Answer 40

– Start 100mg daily
– increased every 3-4 weeks according to response to achieve
decrease serum urate levels (target sUA <300µmol/L)
– Usual maintenance 300mg daily (100-600mg)
– Accumulate in renal impairment (Dose 50-100mg
daily)

Question 41

what are some side effects of allopurinol?

Answer 41

– Rashes
– Hypersensitivity reactions
– Gastrointestinal disturbances

Question 42

what is febuxostat? how it works, dose, side effects?

Answer 42

⚫Alternative to allopurinol if intolerant or C/I (NICE2008)
⚫Non-purine selective inhibitor of xanthine oxidase
⚫Dose: 80mg od (↑ to 120mg if uric acid levels
>357μmol/l after 2-4 weeks)
⚫Continue if acute attack occurs during prophylaxis
⚫Side-effects: G.I., headache, ↑LFTs, oedema, rash
⚫Rare but serious hypersensitivity reactions

Question 43

what is the second line for gout?how they work

Answer 43

-URICOSURIC AGENTS e.gSulfinpyrazone, Probenecid (unlicensed),
Benzbromarone (unlicensed),
-⚫ increase uric acid excretion by direct action on renal
tubule
⚫ Avoid in urate nephropathy
⚫ Ineffective in poor renal function (CrCl <20-30
ml/min)
⚫ Need to maintain high fluid intake to decrease risk of
stone formation

Question 44

what is canakinumab?

Answer 44

-very expensive
⚫ S/C injection
⚫ Recombinant monoclonal antibody
⚫ Severe, refractory tophaceous gout (NICE,2013)
⚫ Target interleukin-1ᵝ associated with
inflammatory response induced by urate
crystals
⚫ C/I in current infection – due to risk of sepsis
⚫ Acute flares – not approved by NICE

Question 45

what are some other treatment for gout?

Answer 45

⚫ Pegloticase
– Pegylated uricase, catalysing the oxidation of uric acid into
allantoin (more soluble end product)
– For those with crystal proven, severe debilitating tophaceous gout
and poor QoL where the SUA cannot be reached at fully optimised
treatment
– Not approved by NICE
⚫ Anakinra
– IL-1 receptor antagonist
– Not licensed for gout (licensed for RA)
⚫ Rilonacept
– IL-1alpha/beta antagonist and IL-1R antagonist
– Unlicensed in IK

Question 46

what is an important interaction involing allopurinol?

Answer 46

ALLOPURINOL+AZATHIOPRINE
⚫ Azathioprine metabolised to mercaptopurine
⚫ Mercaptopurine metabolised by Xanthine
oxidase
⚫ Allopurinol causes accumulation ➔
Potentially fatal bone marrow suppression