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Inflammatory and GI diseases > Gout > Flashcards

Gout Flashcards

1
Q

What is gout?

A

It is a group of diseases, characterised by increased levels of uric acid in the blood known as Hyperuricaemia.

  • It is caused by either an increase in the production of uric acid or reduction in the excretion of uric acid or a combination of both.
  • There is deposition of monosodium urate monohydrate crystals in joints and soft tissues and this can eventually result in acute inflammation and eventually tissue damage.
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2
Q

What happens in uric acid synthesis?

A

Uric acid is the end product of purine metabolism.

In the last 2 steps of this process, it is under the control of xanthine oxidase.

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3
Q

How is uric acid excreted?

A
  • Uric acid excretion mainly occurs in the kidneys
  • Uric acid is completely filtered by the glomerulus
  • 90-100% is reabsorbed in the proximal tubule which is controlled by the URAT-1 specific anion transporter.
  • Once its been reabsorbed in the proximal tubule, the 50% is actively secreted back out in the distal tubule
  • But then 40-45% undergoes further secretary reabsorption after that point.

So in the end you end up with around 5-10% of original glomerular load is actually excreted in the urine.

Of the uric acid that is removed from the body in total, about 2/3 of it is actually excreted in the urine. The remaining 1/3 is excreted through the bile in the GI tract.

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4
Q

What is the underlying cause of Gout?

A

Gout is either caused by:

  1. Increase in rate of synthesis of uric acid (occurs in about 10% of cases)
  2. Reduction in the elimination of uric acid by the kidneys (uric acid build up - 90% of cases)
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5
Q

What is primary gout?

A

Due to rare inborn errors of metabolism or renal excretion.

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6
Q

What is secondary gout?

A

Occurs due to drugs or consequence of other disorders

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7
Q

How is gout caused by over consumption?

A

Over consumption of foods that are high in purines therefore associated with triggered gout:

  • Offal (liver, kidney, heart, sweetbreads)
  • Oily fish
  • Seafood
  • Yeast
  • Meat extracts
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8
Q

How is gout caused by over production? (10% of cases)

A

Underlying cause is over production of uric acid. Causes may be:

  • Excessive cell turnover (e.g. neoplastic disease, psoriasis, haemolytic anaemias)
  • Cell lysis caused by cancer chemotherapy and radiotherapy
  • Excessive synthesis or uric acid due to rate enzyme mutation defects
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9
Q

How is gout caused by under excretion? (90% of cases)

A

Hyperuricaemia:
- When theres high levels of uric acid in the blood, normally large urate loads are filtered through the glomerulus due to high levels.

  • This then triggers an increase in urate reabsorption in the proximal tubules to avoid dumping of insoluble urate into urinary tract. -> NORMAL process
  • There’s also a reduction in the tubular secretion in the distal tubule. Hence in the end theres an overall reduction in the excretion of the uric acid.

The situations where you GET under excretion is:

  1. Renal failure -> Kidneys aren’t functioning properly hence they cannot excrete uric acid appropriately.
  2. Alcohol (beer, red wine) -> some forms of alcohol have high levels of purine and when alcohol is broken down in the body it produces purine which produces uric acid and it also reduced uric acid excretion in the urine hence has a direct effect
  3. Drugs:
    - Diuretics -> Especially thiazides (e.g. bendroflumothaizide) and furosemide. They cause volume depletion and a reduction in. tubular excretion of uric acid. Hence causing gout.
  • Other examples -> Aspirin, ciclosporin, omeprazole, ethambutol etc.
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10
Q

What are other triggers/causes of gout?

A
  1. Physical stress on a particular joint:
    - Tight shoes
    - Hill walking
    - Hiking
    - History of joint trauma
  2. Other independent risk factors:
    - Hypertension
    - Obesity
    - Hypertriglyceridaemia
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11
Q

What happens when somebody develops gout?

A

Hyperuricaemia is the most common risk factor:

  1. Uric acid levels:
    - Formation and deposition of monosodium urate crystals is more likely to occur when levels are persistently > 380 micro/mol
  2. Higher the plasma urate level, theres a higher incidence of gout
  3. Prolonged duration of high urate levels, then the likelihood of developing gout.
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12
Q

What are the characteristics of Uric acid?

A
  • Uric acid is a weak acid with a pKa of 5.8
  • At physiological pH it is ionised to monosodium urate (MSU)
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13
Q

How are urate crystals formed?

A

Problem occurs when theres supersaturation within a particular joint and theres formation of crystals.

Their solubility and risk of deposition is influenced by:
- Temperature
- pH
- Cation concentration
- Articular dehydration
- Presence of nucleating agents

Crystal deposition may continue for many months or years without causing symptoms.

You only get symptoms when those crystals are shed into bursa (small sacs of synovial fluid surrounding joint) causing an inflammatory reaction

Shedding can be triggered by:
- Trauma
- Dehydration
- Rapid weight loss
- Illness
- Surgery

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14
Q

How are urate crystals able to initiate, amplify and sustain inflammatory responses?

A

Urate crystals are directly able to imitate, amplify and sustain inflammatory responses through:

  • Humoral and cellular inflammatory mediators
  • Complement system

Then overall this causes:
- A pro inflammatory cascade of cytokines, chemotactic factors, TNF
- Accumulation of inflammatory cells

IL-1 beta has also been shown to be critically related to the inflammatory response in gout.

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15
Q

What are the 5 stages of clinical presentation for gout?

A
  1. Asymptomatic hyperuricaemia
  2. Acute gouty arthritis
  3. Interval gout/intercritical gout
  4. Chronic tophaceous gout
  5. Gouty nephropathy
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16
Q

What is acute gouty arthritis?

A

When you get your first attack of gout.

  • 90% acute attacks are monoarticular (occur in 1 joint)
  • 80% of first attack of gout will occur in the big toe.
  • Can affect other joints: small joints of feet/ankles, hands (distal interphalangeal), elbows and knees
  • All caused by deposition of carte crystals in joints
17
Q

What are the signs and symptoms of acute gouty arthritis?

A
  • Severe pain with hot, red, swollen and extremely painful joints
  • Begins abruptly - max intensity 8-12 hrs
  • Weight bearing impossible
  • Erythema (redness of skin)
  • Synovitis (inflammation of synovial membrane)
  • Leucocytosis (increase in WBC)
  • Confusion in elderly

Attack can be caused by anytime due to trigger factors such as:
- Food
- Alcohol
- Dehydration
- Starting diuretics

If left untreated, it lasts around 7 days and then caused desquamation (peeling) of overlying skin

18
Q

What is intercritical gout?

A

This is where your acute attack of gouty arthritis is followed by variable intervals of between months to years where they have no symptoms at all of gout.

19
Q

What is chronic tophaceous gout?

A

Is where you get the presence of tophi.

Tophi are when you get:

  • White deposits of monosodium urate
  • They appear as nodules on the affecting joint
  • It occurs in subcutaneous and periarticular areas - hence in the skin and around the joint
  • Particularly ear lobes, achilles tendon, fingers etc
20
Q

What is gouty nephropathy / Hyperuricaemia induced renal disease?

A

Crystals of the urate would have deposited around the renal tubules and consequently cause an inflammatory response and ended up with kidney damage.

These patients will often have proteinuria (presence of protein in the urine) and renal impairment.

Sometimes patients will develop renal stone formation. Stones blocking the outflow of the kidneys. The stones are made up of monosodium urate.

21
Q

What can be done for the diagnoses of Gout?

A
  • Has to be based on clinical history and examination
  • Uric acid levels can be useful but are nit always raised when someone has an acute attack
  • Joint fluid microscopy - presence of crystals and absence of infection (NOT ALWAYS DOEN DUE TO RISK OF CAUSING INFECTION)
  • Joint x-ray
  • Standard bloods - RF, lipids, glucose
22
Q

What are the aims of treatment for gout?

A
  • Relieve pain/inflammation of acute attack
  • Terminate attack
  • Prevent further attacks
  • Prevent long term joint and organ damage
  • Avoid precipitating factors
23
Q

How is an acute attack of gout treated?

A
  • Rest - patient should be told to rest
  • Prompt/immediate treatment with full dose of NSAIDs
  • AVOID ASPIRIN - as it competes with uric acid for excretion and can worsen attack
24
Q

How are NSAIDs involved in the treatment of gout?

A

It is a first line choice of treatment

Relieves pain and inflammation

Can abort acute attacks if commenced early enough (patients should carry NSAIDs)

Most important factor is how soon an NSAID is started rather than the choice of NSAIDs given

Full therapeutic high dose for 24-48 hours then lower doses for 7-10 days until completely resolved

Consider gastroprotection e.g. Lansoprazole or Omerprazole

25
Q

When is Colchicine used for the treatment of gout?

A

Used second line when NSAIDs are contraindicated or ineffective.

E.g. CVD, Renal disease, GI toxicity

Colchicine has a slower onset and high levels of toxicity

Colchicine inhibits neutrophil migration into the joint.

Colchicine should be administered ASAP, becomes less effective as time goes on.

26
Q

What dose of Colchicine should be given for gout treatment?

A

0.5mg 2-4 times a day until relief of joint pain or development of GI side effects or total 6mg is taken.

DO NOT repeat course within 3 days

Lower dose of 0.5mg every 8hrs in elderly and patients with renal impairment.

There is response to goat after 6 hrs, pain relief after 12 hrs and resolution after 48-72 hrs.

Interactions ++

Side effects:
- Nausea and vomiting

  • Abdominal pain
  • DIARRHOEA (stop therapy immediately)
  • Rashes, peripheral neuropathy, blood dyscrasias
27
Q

How are corticosteroids involved in the treatment of gout?

A

Oral prednisolone can be given.
Prednisalone 30-35mg daily

Articular: e.g. Triamcinolone
- Consider for mono arthritis for easy accessible joint

28
Q

What is a combination therapy that can be used for gout?

A

NSAID with colchicine or corticosteroid

  • Given for resistant gout
29
Q

How can we prevent/prophylaxis gout attacks from happening in a recurring manner?

A

By the use of Urate Lowering Therapy - ULT.

  • Use of prophylaxis treatment helps avoid further complications such as tophi development or renal failure etc.
  • Prophylaxis treatment is important to prevent long term complication
  • Evidence for when they should be started is quite controversial because initial attacks of gout are often infrequent and self-limiting so at that point exposing the patient to unnecessary medication is not important.
  • CONSIDER ULT when patient suffers from two or more acute attacks per year.
  • They should also CONSIDER ULT if they have any signs of tophi, chronic gouty arthritis, joint damage, renal impairment, urolithiasis (formation of kidney stones), diuretic use and young onset gout attacks.

Traditionally we DO NOT start prophylaxis therapy with ULT during an acute attack because:

  1. Those patients would’ve had hyperuricaemia for couple years so theres no need to actually treat hyperuricaemia immediately if they are undergoing an acute attacks.
  2. Agents used for prophylaxis actually work by reducing uric acid levels. There is evidence to show that changes in uric acid levels (increase or decrease) causes mobilisation of uric acid stores and as a consequence you prolong the attack or precipitate another.
30
Q

What are the benefits of Urate Lowering Therapy?

A
  • Reduces frequency of flares and acute attacks
  • Once crystals are dissolved by the ULT, it tends to avoid recurrence
  • Reduces size and number of tophi
  • Facilitates tophi disappearance
  • Improved quality of life
31
Q

At what dose should ULT be started at?

A

ALL ULT should be started at a LOW dose and titrated upwards

  • Monitor patient symptoms and titrate to serum uric acid (sUA) target.
  • Recommended during the first 6-months of ULT or during a dose titration
  • Colchicine - FIRST LINE
    0.5 - 1mg daily (low dose)
    Reduce dose in renal impaired patients

Where Colchicine is contraindicated or not tolerated:
- Low dose NSAID or COXIB should be considered (consider cautions etc.) + Gastroprotection (e.g lansoprazole or PPI)

32
Q

What is Allopurinol?

A
  • First line choice drug for ULT
  • Controls symptoms
  • Some improvement in tophi (usually after about 6 months of treatment)
  • IT IS A XANTHINE OXIDASE INHIBITOR (Xanthine oxidase controls the last 2 steps of purine production to make uric acid)
  • It is a pro-drug, it undergoes hepatic metabolism to activate metabolite, OXIPURINOL
  • Start Allopurinol 1-2 weeks after acute attack subsided
  • If patient already on Allopurinol at onset of acute attack, then continue on it and treat acute attack at the same time.
  • Allopurinol can be used for prevention of diuretic induced hyperuricaemia (drug induced gout) if no alternative
33
Q

What is the dosing for Allopurinol?

A
  • Starting dose for Allopurinol is 100mg daily
  • Increase dose every 3-4 weeks according to response to treatment to achieve LOW serum urate levels (Target sUA <300umol/L)
  • Usual maintenance 300mg daily (100-600mg)
  • Accumulate in renal impairment (Lower Dose 50-100mg daily)
34
Q

What are the side effects of Allopurinol?

A
  • Rahes
  • Hypersensitivity reactions
  • GI disturbances
35
Q

What is Febuxostat?

A
  • Febuxostat is an alternative (another first line) to allopurinol if intolerant or contraindicated.
  • IT IS ALSO A XANTHINE OXIDASE INHIBITOR

Dose: 80mg OD (can be increased to 120mg if uric acid levels >357umol/l after 2-4 weeks)

  • If patient is already on Febuxostat and suffer an acute attack, you would keep them on it whilst treating that acute attack.

Side effects:
- GI disturbances
- Headache
- Increased LFTs
- Oedema
- Rash
- Rare but serious hypersensitivity reactions

36
Q

What are the Uricosuric agents?

A

Second line treatment in ULT alternative to Allopurinol/Febuxostat.

Examples include:
- Sulfinpyrazone
- Probenecid (unlicensed)
- Benzbromarone (unlicensed)

Mechanism of action:
- They are NOT xanthine oxidase inhibitors
- They INCREASE uric acid EXCRETION by direct action on renal tubule.

They should be AVOIDED if patient has any evidence of urate nephropathy as they can worsen the incidence of kidney stones or crystal formation.

They are INEFFECTIVE in poor renal function (CrCl < 20-30 ml/min)

Need to maintain high fluid intake when on these agents to reduce the risk of stone formation.

Sometimes Uricosuric agents can be used in combination with xanthine oxidase inhibitor if we don’t achieve an appropriate serum urate level with mono therapy.

37
Q

What is Canakinumab?

A
  • It is a subcutaneous injection
  • Made up on recombinant monoclonal antibody
  • Proved by NICE for Sever, refractory tophaceous gout

Mechanism of action:
Targets IL-1 associated with inflammatory response induced by urate crystals

Contraindicated in current infection - due to risk of sepsis (life-threating reaction to an infection)

VERY EXPENSIVE

38
Q

What is an IMPORTANT interaction of Allopurinol?

A

Allopurinol + Azathioprine

  • Azathioprine metabolised to mercaptopurime
  • Mercaptopurine metabolised by Xanthine oxidase
  • Allopurinol causes accumulation -> Potentially fatal bone marrow suppression

Inflammatory and GI diseases (22 decks)

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