Week 3- Gout Flashcards
what is gout?
its a group of diseases of increased levels of uric acid in the blood- HYPERURICAEMIA
what is gout caused by?
increase production or decreased excretion or both
what is happeneing during gout?
- Deposition of monosodium urate
monohydrate crystals in joints & soft tissues
➔ acute inflammation & eventually tissue damage
what is the epidemilogy of gout?
- more common in men 30-60yrs and in older ppl
- more likely if there is family history of it
what is the physiology of gout?
-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
what is the aetiology of gout?
-icnreased rate of synthesis of purine precursors of
uric acid (10%)
- decreased elimination of uric acid by kidney (90%)
what are the 2 types of gout?
-Primary:
– Due to rare inborn errors of metabolism or renal
excretion (not covered here)
- Secondary:
– Occur due to drugs or consequence of other
disorder
what is the explantation of gout due to over consumption of uric aicd?
-Offal (liver, kidney, heart, sweetbreads), game,
oily fish (anchovies, herring, mackerel, sardines,
sprats, trout), seafood, yeast or meat extracts.
what is the explantation of gout due to over production of uric acid?
⚫ 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
what is the explantation of gout due to under excretion of uric acid?
Hyperuricaemia ➔ large urate loads filtered
through glomerulus ➔ increased urate reabsorption
to avoid dumping of insoluble urate into
urinary tract
-Also reduction tubular secretion
what type of situation would you get under excretion of uric acid?
-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
what are other causes for gout and risk factors?
⚫ Physical Stress
– Tight shoes, hill walking, hiking, history of joint
trauma
⚫ Other independent risk factors: hypertension,
obesity & hypertriglyceridaemia
what is the gout pathophysiology?
– 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.
when is uric acid a probelm?
-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)
when may a patient have symptoms of gout?
-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
what are some symptoms that a patient might experience?
Shedding can be triggered by e.g:
– Trauma, dehydration, rapid weight loss, illness &
surgery
what do the urate crystals do once they are in the bursa?
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
what are the 5 stages clinical presentation of gout?
– Asymptomatic hyperuricaemia (long period before gout manifests) – Acute gouty arthritis – Interval gout/Intercritical gout – Chronic tophaceous gout – Gouty nephropathy
what is acute gouty arthritis?
-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
what are some signs and symptoms of gout?
⚫ 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
when do attacks of gout happen?
⚫ 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
what is intercritical gout?
⚫ Time between acute attacks of gout
⚫ Variable intervals of months to years when
there are no symptoms
what is chronic tophaceous gout?
⚫ 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
what is Gouty nephropathy/ Hyperuricaemia
induced renal disease?
⚫ Crystals of urate deposited around renal tubules ➔ inflammatory response (interstitial nephritis) ⚫ Proteinuria & renal impairment ⚫ Renal stone formation
how is gout diagnosed?
⚫ 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
what are the aims for the treatment of gout?
⚫ Relieve pain/inflammation of acute attack
⚫ Terminate attack
⚫ Prevent further attacks
⚫ Prevent long term joint and organ damage
⚫ Avoid precipitating factors
what should a patient do if they get an acute attack?
-rest
-prompt treatment with full dose NSAIDs
-avoid ASPIRIN, – Competes with uric acid for excretion and can
worsen attack
what is the first line treatment for gout?
-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
what is the second line treatment for gout?
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
what are some interaction for colchicine?
-glycoprotein inhibitor
what are some side effects of colchicine?
– Nausea & vomiting
– Abdominal pain
– Diarrhoea (stop therapy immediately)
– Rashes, peripheral neuropathy, blood dyscrasias these are rare
what is other treatment for gout
⚫ 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
what is combination therapy for got?
NSAID with colchicine or corticosteroid
how does prophylaxis(Urate Lowering Therapy – ULT) help gut?
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
why dont you start prophylaxis during an acute attack?
⚫ 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
what does Urate Lowering TherapY do?
– Reduces frequency of flare – Once crystals dissolved avoids recurrence – Reduces size and number of tophi – Facilitates tophi disappearance ⚫ IMPROVED QoL
when is colchicine used as first line?
-when using prophylaxis AT A DOSE OF 0.5-1mg daily
if CI use low NSAIDS AND ppi
What is used first line for ULR?
allopurinol
⚫ Controls symptoms
⚫ Some improvement in tophi (usually after
about 6 months treatment)
what is the mechanism of action for allopurional?
⚫ Xanthine oxidase inhibitor
⚫ Pro-drug ➔ undergoes hepatic metabolism
to active metabolite, oxipurinol
what dose of allopurinol is used?
– 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)
what are some side effects of allopurinol?
– Rashes
– Hypersensitivity reactions
– Gastrointestinal disturbances
what is febuxostat? how it works, dose, side effects?
⚫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
what is the second line for gout?how they work
-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
what is canakinumab?
-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
what are some other treatment for gout?
⚫ 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
what is an important interaction involing allopurinol?
ALLOPURINOL+AZATHIOPRINE
⚫ Azathioprine metabolised to mercaptopurine
⚫ Mercaptopurine metabolised by Xanthine
oxidase
⚫ Allopurinol causes accumulation ➔
Potentially fatal bone marrow suppression
