Gout

Question 1

what type of an arthritis is gout?

Answer 1

a crystal arthritis

Question 2

clinical syndrome of gout

Answer 2

monosodium urate (MSU) crystal deposition

Question 3

physiologic syndrome of gout

Answer 3

hyperuricemia

Question 4

hyperuricemia

Answer 4

excess urate in the plasma that may or may not result in precipitation of uric acid crystals. >6.8 mg/dl

Question 5

most common form of inflammatory arthritis?

Answer 5

gout

Question 6

who does gout mostly affect?

Answer 6

middle aged men

Question 7

why doesn’t gout affect pre-menopasual women?

Answer 7

estrogen promotes renal uric acid excretion

Question 8

risk factors for gout

Answer 8

obesity, metabolic syndrome, hypertension, insulin resistance, purine rich diet, alcohol

Question 9

role of PRPP synthase

Answer 9

conversion of ribose 5P to PRPP

Question 10

role of PRPP in gout

Answer 10

increased activity leads to increased PRPP (X linked mutation) that leads to increased uric acid (hyperuricemia)

Question 11

HGPRT role

Answer 11

catalyzes single step salvage reaction for guanine and hypoxanthine.

Question 12

HGPRT in gout

Answer 12

enzyme deficiency leads to higher levels of guanine and hypoxanthine –> hyperuricemia

Question 13

uricase

Answer 13

enzyme not present in humans, catalyzes the conversion of uric acid to soluble allantion, leading to lower levels of uric acid

Question 14

recombinant uricase used for gout treatment

Answer 14

pegloticase

Question 15

xanthine oxidase role

Answer 15

catalyzes oxidation of hypothanxine to xanthine and xanthine to uric acid

Question 16

xanthine oxidase in gout

Answer 16

inhibition decreases uric acid level

Question 17

drugs targeting XO

Answer 17

allopurinol & febuxostat

Question 18

circulating uric acid

Answer 18

urate anion

Question 19

limit of solubility for serum urate anions

Answer 19

6.8mg/dL

Question 20

where is uric acid produced?

Answer 20

liver (from degradation of purine compounds)

Question 21

sources of urate production

Answer 21

not direct (always from liver metabolism of purine compounds). 
dietary intake, tissue nucleic acids, endogenous purine synthesis

Question 22

urate excretion

Answer 22

GI (1/3) and renal (2/3)

Question 23

URAT1 (urate/organic anion exchanger)

Answer 23

highly urate specific anion exchanger (organic anions) that is responsible for the reabsorption of filtered urate

Question 24

where is URAT1?

Answer 24

on the luminal membrane of proximal renal tubular epithelial cells.

Question 25

stimulation of URAT1

Answer 25

increased irate absorption and hyperuricemia

Question 26

inhibition of URAT1

Answer 26

decreased irate absorption, hypouricemia

Question 27

drug that inhibits URAT1 and causes more uric acid secretion in urine (uricosuria)

Answer 27

probenecid

Question 28

is hyperuricemia more likely due to overproduction or under excretion?

Answer 28

90% underexcretion

Question 29

causes of irate overproduction

Answer 29

primary and secondary hyperuricemia

Question 30

primary hyperuricemia

Answer 30

inherited defects in regulation of purine nucleotide synthesis (HGPRT deficiency and PRPP synthetase super activity)

Question 31

secondary hyperuricemia

Answer 31

dietary consumption, increased nucleic acid turnover (MPNs), accelerated ATP degradation

Question 32

causes of irate underexcretion

Answer 32

kidney disease , medications, stimulation of URAT1

Question 33

how does alcohol affect homeostasis of urate pool?

Answer 33

overproduction: increases plasma concentration of purines due to liver metabolism underexcretion: stimulates URAT1 via increased lactic acid fro fermentation, dehydration inhibits excretion

Question 34

pathogenesis of gout-basic version

Answer 34

uric acid crystals are mobilized and shed into synovial fluid, which causes a very strong inflammatory response

Question 35

pathogenesis of gout- detailed version

Answer 35

crystal phagocytosis by synovial cells leads to the activation of the NALP3 inflammasome, which releases IL-1B, which binds to IL1 in synovial cells, which activates NF-kB which in turn increases secretion of cytokines that cause neutrophil activation and acute inflammation

Question 36

IL-1B

Answer 36

inflammatory cytokine produced and released by NALP3 inflammasome complex

Question 37

MSU crystals and complement

Answer 37

crystals can directly activate the C5b-9 complex that leads to mediator production involved in systemic symptoms like fever, high white count, etc

Question 38

how does gout spontaneously resolve?

Answer 38

mediators either undergo death/deactivation/differentiation and lose inflammatory function, or up regulation of anti-inflammatory cytokines, or increased vascular permeability leads to urate transport out/increased entry of anti-inflammatory molecules

Question 39

asymptomatic hyperuricemia

Answer 39

elevation of serum urate concentration in absence of signs of gout. 2/3s of hyperurimic patients

Question 40

acute gout

Answer 40

acute onset, maximal severity within 12-24 hrs. severe pain, redness, swelling, disability. monoarticular

Question 41

which joints are most commonly affected in acute gout?

Answer 41

hallux and knee

Question 42

hallux involvement in gout

Answer 42

podagra

Question 43

pseudogout

Answer 43

crystals of calcium pyrophosphate

Question 44

chronic tophaceous gout

Answer 44

chronic hyperuricemia with recurrent acute flares. persistence of synovial fluid crystals with low grade inflammation. presence of tophi and erosions

Question 45

tophi

Answer 45

deposits of MSU crystals. nests of crystals enveloped by granuloma like chronic inflammatory response with macrophages and multi nucleated giant cells, encased by dense connective tissue

Question 46

urolithiasis

Answer 46

uric acid kidney stones. precipitation of crystals in the collecting ducts and ureters

Question 47

acute uric acid nephropathy

Answer 47

uric acid precipitation within the renal tubules or interstititum. causes acute renal failure

Question 48

synovial fluid aspirate diagnostic of gout

Answer 48

needle shaped, negatively birefringent (yellow=parallel, blue=perpendicular)

Question 49

treatment for acute gout

Answer 49

control acute inflammation with non steroidal anti-inflammatory meds, colchicine, glucocorticoids

Question 50

colchicine

Answer 50

blocks activation of NALP3 inflammasome, inhibits neutrophil activation in response to crystals

Question 51

treatment from chronic gout

Answer 51

decrease uric acid levels with XO inhibitors (allopurinol), uricase (pegloticase), and URAT1 agents (probencid) or via lifestyle modification (decreased purine intake)