ChemPath: Hyperuricaemia and Gout

Question 1

What are purines?

Answer 1

Ubiquitous Biomolecules

Adenosine, Guanosine and Inosine

Question 2

What are the 3 important biological roles purines?

Answer 2

Genetic code A & G

Second messengers for hormone action in the form of cAMP and cGMP

Energy transfer/stores as ATP and GTP

Question 3

What is the prevalence of gout?

Answer 3

3% of males have gout sometime in life. Lower prevalence in females.

Question 4

Describe purine catabolism.

Answer 4

Purine is broken down into hypo-xanthine.

Hypo-xanthine is sequentially oxidised to xanthine by XANTHINE OXIDASE. Then oxidised to urate.

Question 5

What is the difference between human and cow purine metabolism?

Answer 5

Cows (and other animals) have enzyme Uricase which converts urate to allantoin which is highly soluble and freely excreted in the urine.

Homosapiens have an inactive mutation of uricase.

Urate is relatively insoluble.

Question 6

Urate is relatively _______ . It circulates in blood streams at a concentration close to its ______ of _______ . It is constantly on the brink of ________ out and forming ______ ______ _________ which are the aetiology of gout.

Answer 6

Urate is relatively insoluble. It circulates in blood streams at a concentration close to it limit of solubility. It is constantly on the brink of precipitating out and form uric acid crystals which are the aetiology of gout.

Question 7

What are the normal plasma concentrations of monosodium urate?

Answer 7

Men 0.12 - 0.42 mmol/l

Women 0.12 - 0.36 mmol/l

Question 8

What does solubility of urate depend on?

Answer 8

Temperature and pH.

Solubility at 37oC = 0.40 mmol/l At 30oC = 0.27 mmol/l

Lower pH –> solubility decreases

Cooler temperatures –> solubility decreases

This may be why the first MTP joint is the first to be affected - cooler temperature on the extremities

Question 9

Describe renal urate handling.

Answer 9

Tubular urate handling leads to high concentration of urate.

Uric acid is reabsorbed and re-excreted at the PCT → 90% gets reabsorbed

Question 10

What is the FEUA?

Answer 10

Fractional Excretion of Uric Acid is about 10%.

90% is reabsorbed which keeps the uric acid levels in circulation high and close to its limit of solubility,

Question 11

What are the two main ways of purine synthesis?

Answer 11

De novo synthesis - this is metabolically hard work, insufficient in terms of energy use

Salvage pathway - highly energy efficient. Recycles purines. Vast majority of purine synthesis via salvage pathway.

Question 12

Which tissue does the de novo purine pathway dominate?

Answer 12

Bone marrow

Question 13

What is the rate-limiting step in de novo purine synthesis? What are the positive and negative feedback mechanisms of this rate-limiting step?

Answer 13

The reaction catalysed by PAT enzyme is the rate-limiting step.

The outputs of the enzyme PAT are AMP and GMP which exert a negative feedback on PAT.

If PRPP levels increase this provides positive feedback on PAT.

Question 14

What is the main enzyme in the purine salvage pathway?

Answer 14

HGPRT

Question 15

What does HGPRT do?

Answer 15

It scoops up partially catabolised purines and brings them back to the metabolic pathways of IMP and GMP.

Question 16

What is Lesch-Nyhan syndrome?

Answer 16

Complete HGPRT deficiency. It is an X-linked disease. No HGPRT means you cannot do the salvage pathway of purine metabolism.

Question 17

What are the characteristics of Lesch-Nyhan syndrome?

Answer 17

• Normal at birth
• Developmental delay apparent at 6-12 months
• Hyperuricaemia
• Choreiform movements (1 year)
• Spasticity, mental retardation
• Self mutilation (85%) aged 1-16

Question 18

Describe the pathology of Lesch-Nyhan syndrome.

Answer 18

HGPRT is missing so no guanine or hypoxanthine can be recycled back to GMP and IMP respectively.

Lack of negative feedback from GMP and IMP on PAT means the de novo pathway goes into overdrive → lots of IMP → catabolised into lots of urate

PRRP also builds up which has a positive feedback effect on PAT

Question 19

How many causes of hyperuricaemia be divided?

Answer 19

1. Increased urate production
2. Decreased urate excretion

Each of these can be divided into primary and secondary causes. Secondary increased urate causes are due to conditions where there is so much cell division/turnover that you overload the body’s ability to excrete urate.

Question 20

What are some causes of decreased urate excretion?

Answer 20

FJHN, chronic renal failure, Barrter’s syndrome, Saturnine gout (lead poisoning), thiazides.

Question 21

In purine metabolism:

1. The salvage pathway predominates over de-novo synthesis in most tissues
2. Xanthine oxidase oxidises xanthine to uric acid
3. HPRT is deficient in Lesch-Nyhan disease
4. PAT (PRPP Amino Transferase) is the rate limiting enzyme
5. PAT is under –ve feedback control from AMP and GMP
6. All of the above

Answer 21

6. All of the above

Question 22

What crystals are found in Gout?

Answer 22

Monosodium urate crystals

Question 23

What are other names of acute and chronic gout?

Answer 23

Acute = Podagra

Chronic = Tophaceous

Question 24

What is the prevalence of gout in males and females?

Answer 24

Males 0.5 - 3%

Females 0.1 - 0.6%

Most common in post pubertal males and post menopausal females

Question 25

Describe the pathology of gout.

Answer 25

When the limit of solubility drops below the prevailing concentration, precipitation occurs forming needle-shaped crystals which are powerful inflammatory stimuli for neutrophils and macrophages. These set up an intense immune reaction in the synovial of the joint.

Question 26

In chronic gout (tophaceous) you get cumulative deposition of uric acid in ______ ______. These can be _________ (next to joints such as in the fingers). Classically tophi deposits are found in the ___ ______. It looks like hard cheese.

Answer 26

In chronic gout (tophaceous) you get cumulative deposition of uric acid in soft tissue. These can be periarticular (next to joints such as in the fingers). Classically tophi deposits are found in the ear lobe. It looks like hard cheese.

Question 27

What are the clinical features of acute gout?

Answer 27

• Rapid build up of pain
• Exquisite
• Affect joint red, hot and swollen
• 1st MTP joint first site in 50%
• This joint is involved in 90% overall

Question 28

What should you NOT do in management of acute gout?

Answer 28

Do not try to lower plasma urate levels in acute gout attacks. Paradoxically, acutely changing plasma urate levels can lead to further precipitation of crystals.

Question 29

What is the management of acute gout?

Answer 29

Main aim is to reduce inflammation.

- NSAIDS (diclofenac)

- Colchicine - inhibits polymerisation of tubulin. This inhibits microtubule assembly. Microtubules are needed for mitosis and motility of neutrophils. Decreased microtubule assembly means fewer neutrophils moving int the joint and reacting with crystals to set off and inflammatory reaction.

- Glucocorticoids - can massively decrease inflammation and may be injected into the joint or given systemically as prednisolone tables.

Question 30

Once an acute attack is over, hyperuricaemia may be managed. How is hyperuricaemia managed?

Answer 30

Management of chronic gout:

• Drink a lot of water
• Reverse factors putting up urate
• Reduce synthesis will allopurinol (xanthine oxidase inhibitor)
• Increase renal excretion with probenecid: uricosuric

Question 31

What are the side effects of allopurinol?

Answer 31

• Interacts with azathioprine, making it more toxic on bone marrow.
• Azathioprine is metabolised to mercaptopurine and then to thioinosinate which interferes with purine metabolism
• Allopurinol makes the mercaptopurine last longer

Question 32

In the treatment of Gout: 1. Allopurinol should be used acutely 2. NSAIDs are the first line treatment in acute attacks 3. Colchicine lowers urate levels 4. Allopurinol lowers urate levels by inhibiting HPRT 5. Allopurinol lowers urate levels by inhibiting xanthine oxidase

Answer 32

2. NSAIDs are the first line treatment in acute attacks 5. Allopurinol lowers urate levels by inhibiting xanthine oxidase

Question 33

How is gout diagnosed?

Answer 33

Tap effusion of joint

View effusion under polarised light

Use a red filter

Question 34

What do you expect to see under polarised light microscopy with monosodium urate monohydrate crystals?

Answer 34

Urate crystals are negatively birefringent needle-shaped crystals. Negatively birefringent waves show up as blue perpendicular to the compensator filter axis and yellow parallel to the filter axis.

Question 35

What do you expect to see under polarised light microscopy with pyrophosphate crystals?

Answer 35

Pyrophosphate crystals are positively birefringent. They are blue parallel to the axis of the compensator filter and yellow perpendicular to the filter axis.

Question 36

In what sort of patients does pseudogout occur in?

Answer 36

Patients with osteoarthritis. It is self limiting 1 - 3 weeks.

Question 37

What sort of crystals are found in pseudogout?

Answer 37

Pyrophosphate

Question 38

What joints are affected in pseudogout?

Answer 38

Joints all around the body. Typically it affects the knee.