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.

Question 6

Why does urate deposit and cause gout?

Answer 6

Urate is relatively insoluble

It circulates in the bloodstream at a concentration close to its limit of solubility –> AKA constantly on the brink of precipitating out

As it can precipitate out easily, it can 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

NOTE: lower concentrations in women may be why women have a lower incidence of gout

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

NOTE: 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

Urate freely filtered in glomerulus
In the PCT, the uric acid is reabsorbed then some of it is re-excreted → 90% gets reabsorbed, 10% excreted into the filtrate

Tubular urate handling leads to high concentration of urate.

Question 10

What is the FEUA?

Answer 10

Fractional Excretion of Uric Acid (AKA the amount of uric acid in the renal filtrate) is about 10%.

90% is reabsorbed which keeps the uric acid levels in circulation high and close to its limit of solubility.
(Hypothesised uric acid is an important antioxidant.)

Question 11

What are the two main ways of purine synthesis?

Answer 11

REMINDER: purines are ubiquitous biomolecules (Adenosine, Guanosine and Inosine) which are converted/oxidised to urate.

1. De novo synthesis - occurs in the bone marrow, this is metabolically hard work, insufficient in terms of energy use
2. Salvage pathway - highly energy efficient. Recycles purines. Vast majority of purine synthesis via salvage pathway.

Question 12

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 12

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 13

What is the main enzyme in the purine salvage pathway?

Answer 13

HGPRT (same enzyme as HPRT) –> it scoops up partially catabolised purines and brings them back to the metabolic pathways of IMP and GMP

Question 14

What is Lesch-Nyhan syndrome?

Answer 14

• Complete HGPRT deficiency
• It is an X-linked disease –> almost exclusively affects MALES
• No HGPRT means you cannot do the salvage pathway of purine metabolism

Question 15

What are the characteristics of Lesch-Nyhan syndrome?

Answer 15

• Normal at birth
• Developmental delay apparent by 6 months
• Hyperuricaemia
• Choreiform movements at around 1 year
• Spasticity, mental retardation
• Self mutilation (85%) aged 1-16 –> bite their lips / digits to injure them

Question 16

Describe the pathology of Lesch-Nyhan syndrome.

Answer 16

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 17

How many causes of hyperuricaemia be divided?

Answer 17

1. Increased urate production
2. Decreased urate excretion

Each of these can be divided into primary and secondary causes

NOTE: 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 18

Causes of increased urate production:

Answer 18

Primary causes:
* Lesch-Nyhan Syndrome
* Partial HRPT deficiency
* Glycogen storage disorders
* PRPP synthase overactivity
* Fructose intolerance

Secondary causes:
* Myeloproliferative disorders
* Lymphoproliferative disorders
* Chronic haemolytic anaemia

Question 19

Causes of decreased urate excretion:

Answer 19

• FJHN (Familial juvenile hyperuricaemic nephropathy) - primary cause

Secondary causes:
* Chronic renal failure (AKA CKD)
* Barrter’s syndrome
* Saturnine gout (lead poisoning)
* Diuretics e.g. thiazides
* Aspirin

Question 20

In purine metabolism (SUMMARY):

Answer 20

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

Question 21

What is gout?

Answer 21

Crystal arthropathy caused by monosodium urate crystals (needle shaped) –> leads to inflammatory reaction in the synovial of the joint

Acute gout (Podagra) –> acute arthropathy

Chronic gout (Tophaceous) –> chronic + accumulative deposition of crystals, often peri-articular (next to the joint e.g. in the fingers) or in the earlobe (cheese-like appearance of the deposits)

Question 22

What is the prevalence of gout in males and females?

Answer 22

Males 0.5 - 3%

Females 0.1 - 0.6%

Most common in post pubertal males and post menopausal females

Question 23

Describe the pathology of gout.

Answer 23

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

Question 24

What are the clinical features of acute gout?

Answer 24

• Rapid build up of pain
• Affected joint red, hot and swollen
• 1st MTP joint first site in 50% (and involved in 90% overall)

Question 25

What should you NOT do in management of acute gout?

Answer 25

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 26

What is the management of acute gout?

Answer 26

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 into the joint and reacting with crystals to set off the inflammatory reaction.

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

Question 27

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

Answer 27

Management of chronic gout:

• Drink a lot of water
• Reverse factors that increase circulating urate e.g. diuretics
• Reduce synthesis with allopurinol (xanthine oxidase inhibitor)
• Increase renal excretion with probenecid –> “uricosuric” (increases FEUA)

Question 28

What are the side effects of allopurinol?

Answer 28

• 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 (and build up).

Question 29

How is gout diagnosed?

Answer 29

Tap effusion of joint

View effusion under polarised light

Use a (red) compensator filter

NEGATIVELY BIREFRINGENT NEEDLE SHAPED CRYSTALS

Question 30

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

Answer 30

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 31

What do you expect to see under polarised light microscopy with calcium pyrophosphate dihydratecrystals (AKA pseudogout)?

Answer 31

Pyrophosphate crystals are Positively birefringent
They are blue parallel to the axis of the compensator filter and yellow perpendicular to the filter axis (aka opposite of the gout crystals)

Question 32

What is pseudogout and in what patients does it occur in?

Answer 32

• Occurs in patients with osteoarthritis
• Can affect any joint around the body, BUT most commonly affecting the knee
• Caused by pyrophosphate crystals
• It is self-limiting (1 - 3 weeks)