Pathophysiology of gout and hyperuricaemia

Question 1

what is hyperuricaemia?

Answer 1

A condition associated with increased uric acid levels in the body

Question 2

what two things cause hyperuricaemia?

Answer 2

• Increased intake or production of purines

* Impaired excretion of uric acid by kidneys

Question 3

what is gout?

Answer 3

Inflammatory ‘metabolic’ arthritis associated with chronic hyperuricaemia which may be deposited in arteries as urate crystals.

Question 4

what does uricase do?

Answer 4

convert uric acid to allantoin which is soluble

Question 5

what is the dominant cause of hyperuricaemia in people with gout?

Answer 5

Underexcretion of urate

Question 6

what do urate transportasome’s do?

Answer 6

they are reuptake transporters of urate from the filtered urine in the renal proximal tubule.
-so excess reuptake = hyperuricaemia

Question 7

What effect does the multidrug transporter (ATP-binding cassette transporter G2; ABCG2) have on the urate excretion with reduced function?

Answer 7

• with reduced function, it blocks excretion and contributes to underexcretion

Question 8

what is primary gout?

Answer 8

-not caused by another disorder and is often accompanied by other conditions e.g. obesity, alcohol, hypertension

Question 9

what is secondary gout?

Answer 9

-Develops in course of other disorders e.g. Renal failure

Question 10

what factors influence the precipitation of urate in joints?

Answer 10

1. temperature
2. pH
3. cation concentration
4. articular dehydration
5. presence of insoluble collagen
6. proteoglycans

Question 11

what causes an acute flare of gout?

Answer 11

• The production of mature interleukin 1β (IL1β) after activation of NLRP3 (NALP3) inflammasome occurring after ingestion of crystals by monocytes
• this requires a second signal from toll-like receptor (TLRs).

Question 12

how are flares resolved?

Answer 12

-the neutrophil extracellular trap (NET) binds to the crystals forming a tophi

Question 13

what happens in chronic tophaceous gout?

Answer 13

there is a long period of silence before a flare reoccurs

Question 14

What environmental factors influence gout formation?

Answer 14

1. diet
2. Alcohol intake
3. Adiposity and Insulin resistance

Question 15

how does diet affect gout?

Answer 15

-diets high in purine (e.g. meat and fish increases risk of gout as purine is used to make uric acid

Question 16

what food high in purine is not associated with increased gout risk?

Answer 16

vegetables that are purine-rich

-reason is unknown

Question 17

how does alcohol increase gout risk?

Answer 17

it increases uric acid production and decreases the amount excreted in urine and prevents metabolic acidosis

Question 18

how does adiposity and Insulin Resistance increase gout risk?

Answer 18

-it increases uric acid levels as insulin reduces renal excretion of urate.

Question 19

what are the two approaches to treating gout?

Answer 19

1. Symptomatic Treatment (i.e. inflammation and pain)

2. Reduction of Uricaemia (by reducing uric acid production)

Question 20

What drugs or drug class is used to prevent uric acid production?

Answer 20

Drug class = Xanthine oxidase inhibitors

Drugs = allopurinol, febuxostat

Question 21

What drugs or drug class is used to prevent inflammation?

Answer 21

Drug class = inflammation inhibitors

Drugs = NSAIDs, colchicine, steroids, IL-1 inhibitors

Question 22

What drugs or drug class is used to promote uric acid excretion in the urine as uricosuria?

Answer 22

Drug class = Uricosurics

Drugs = probenecid, benzbromarone

Question 23

What drugs or drug class is used to promote the removal of excess uric acid in the blood and store as allantoin to remove from the body?

Answer 23

Drug class = Uricases

Drugs = rasburicase, pegloticase

Question 24

how does colchicine help with gout?

Answer 24

• helps to prevent inflammation or further inflammation

- has no effect on the uric acid concentration itself

Question 25

how does Xanthine Oxidase Inhibitors work to help with gout?

Answer 25

they prevent uric acid production by inhibiting xanthine oxidase from converting xanthine to uric acid

Question 26

what’s the difference between febuxostat and allopurinol?

Answer 26

-febuxostat is not a purine analogue like allopurinol so it doesn’t affect any other enzyme in the purine metabolic pathways

Question 27

what is the risk with taking sulfinpyrazone in the early stages of gout?

Answer 27

• there is a risk of precipitation of uric acid crystals in kidney
• can therefore block the kidney and form kidney stones

Question 28

how do we reduce the risk of kidney stones in those taking sulfinpyrazone?

Answer 28

• maintain high fluid intake

- keep urine alkaline (uric acid+alkaline urine = neutralisation reaction = water is formed)