Gout Pathophysiology

Question 1

What are the most common risk factors associated with gout?

Answer 1

(1) increase age
(2) male gender
(3) high BP
(4) high SCr/BUN
(5) high body weight
(6) alcohol intake

Question 2

Describe the basic pathophysiology of gout.

Answer 2

Increased serum uric acid levels lead to deposits in the synovium of joints. It is a type of inflammatory arthritis.

Question 3

A uric acid level above ______ is considered hyperuricemia.

Answer 3

6.8 mg/dL

Question 4

The conversion of hypoxanthine to xanthine to uric acid is all catalyzed by what enzyme? What drugs target this enzyme and inhibit it in the treatment of gout?

Answer 4

xanthine oxidase

allopurinol and febuxostat

Question 5

How do we normally get rid of uric acid? How can this be used therapeutically in its treatment?

Answer 5

normally renally excreted

this process can be accentuated therapeutically by uricosurics like probenecid

Question 6

De novo synthesis of purines is accomplished by which enzyme?

Answer 6

PRPP synthetase

Question 7

Decreased activity of which enzyme in the purine salvage pathway can result in increased uric acid levels?

Answer 7

HGPRTase

HGPRTase deficiency increases oxidation of hypoxanthine and increases de novo purine synthesis by PRPP.

Question 8

Describe the basic inflammatory response that occurs in response to deposition of monosodium urate (MSU) crystals in the synovium.

Answer 8

MSU binds to TLRs on the surface of monocytes. They ingest the crystals and activate the inflammasome. IL-1 beta is released, resulting in release of pro-inflammatory mediators. This activates neutrophils and a positive inflammatory feedback loop.

Question 9

What are the 4 developmental stages of gout?

Answer 9

(1) asymptomatic hyperuricemia
(2) acute gout
(3) intercritical phase (10% may never have another attack)
(4) chronic gout

Question 10

How are each of the 4 developmental stages of gout treated?

Answer 10

(1) no treatment
(2) NSAIDS, colchicine, corticosteroids
(3) no treatment
(4) XOI, Pegloticase, Probenecid

Question 11

What are two ways by which a patient can develop high uric acid levels? How can we tell which category the patient falls under?

Answer 11

either overproduction or under-excretion of uric acid

To distinguish, place patient on purine free diet for 3-5 days and measure the amount of uric acid excreted in the urine in 24 hours. If <600 mg on a purine free diet, the patient is an underexcretor. If >1000 mg on a normal diet, the patient is an overproducer.

Question 12

Which classes of diuretics can cause hyperuricemia?

Answer 12

thiazides and loops

Question 13

What is the gold standard diagnostic tool for gout?

Answer 13

actual visualization of tophi present in the joints

Question 14

What are some clinical observations that can support a diagnosis of gout?

Answer 14

monoarticular involvement, pain/swelling/fever, big toe involvement, > 1 attack, hyperuricemia, peak inflammation w/in one day

Question 15

Name and describe the long-term complications associated with gout.

Answer 15

(1) uric acid nephrolithiasis - low urine pH promotes crystal formation in urine resulting in stones
(2) acute or chronic gouty nephropathy - short or long term deposition of urate crystals in the renal system leading to acute renal failure, proteinuria, etc.
(3) tophaceous gout - deposition of MSU crystals in big toe, helix of ear, bursae, knees, wrists, hands resulting in joint pain and destruction

Question 16

colchicine MOA

Answer 16

binds to intracellular protein tubulin and prohibits microtubule proliferation in immune cells to decrease migration and phagocytosis – decreased pain and inflammation

Question 17

colchicine drug interactions

Answer 17

Cyclosporine, Tacrolimus, Verapamil

Question 18

two drug classes used in treatment of acute gout

Answer 18

NSAIDs and corticosteroids

Question 19

Why are NSAIDs preferred over colchicine?

Answer 19

less toxicity

Question 20

Which corticosteroid is primarily used orally in acute gout treatment? Intra-articularly?

Answer 20

orally - prednisone

intra-articular - triamcinolone

Question 21

What are the three main classes of drugs used in prevention of gout (urate lowering therapy)?

Answer 21

xanthine oxidase inhibitors (Allopurinol, Febuxostat)
Uricosurics (Probenecid)
Uricase agents (Pegloticase)

Question 22

Explain how aspirin can precipitate an acute gout attack.

Answer 22

by competing with uricosurics for the anionic transporter in the renal tubules, they decrease the effects of uricosurics

salicylates in general interfere with the excretion of uric acid

Question 23

Probenecid blocks the renal excretion of other drugs such as (name 3 classes)?

Answer 23

cephalosporins, penicillins, sulfonamides

Question 24

Explain how cytotoxic drugs can precipitate an acute gout attack.

Answer 24

Cytotoxic agents cause cell death and the release of nucleic acids into the blood. This increases purine levels and eventually uric acid levels.

Question 25

When may febuxostat be advantageous over allopurinol in gout patients?

Answer 25

patients who are hypersensitive to allopurinol, patients with poor renal function, patients not responding to high doses of allopurinol

Question 26

Pegloticase is contraindicated in which patients?

Answer 26

those with G6P deficiency

Question 27

Give two examples of uricase agents used in treatment of gout.

Answer 27

Pegloticase and Rasburicase

Question 28

Lesinurad (Zurampic) MOA

Answer 28

selective blockade of the URAT1 (urate) transporter in the kidney, preventing reabsorption and enhancing excretion of uric acid