Gout + Drugs B&B

Question 1

what occurs in gout?

Answer 1

monosodium uric acid deposits in joints, crystals are phagocytosed by macrophages/neutrophils —> inflammatory response triggered, recurrent attacks of acute arthritis

Question 2

what are the 3 conditions needed to allow gout to develop?

Answer 2

1. hyperuricemia
2. cool temperatures (feet)
3. genetic disposition

Question 3

podagra

Answer 3

gout occurring in the base of the great toe (1st metatarsophalangeal joint), most common location

Question 4

what causes chronic tophaceous gout?

Answer 4

tophi = uric acid collections in connective tissue (due to repetitive gouty arthritis)

occur in ears, tendons, bursa - not painful, but form small bumps

seen with long-standing hyperuricemia

Question 5

what causes urate nephropathy?

Answer 5

renal conditions caused by gout —> uric acid crystals in urine, uric acid kidney stones, chronic renal failure

Question 6

what are common triggers of primary gout attacks?

Answer 6

primary gout - overproduction of uric acid

attacks triggered by diet (red meat, seafood) and alcohol, also trauma/surgery (due to tissue breakdown)

Question 7

how do purines become uric acid, as occurs in gout?

Answer 7

purines —> hypoxanthine —> uric acid via xanthine oxidase

this is why red meat and seafood can trigger gout attacks, due to the high purine content!

Question 8

explain how alcohol can trigger gout attacks?

Answer 8

alcohol metabolism consumes ATP… adenosine is a purine, which is broken down to uric acid

alcohol metabolism also produces lactic acid, which activates the urate transporter 1 (URAT1) in the kidneys, increasing reabsorption of uric acid

Question 9

Pt is a 45yo M with a BMI of 37 presenting with joint pain in the knee, which occurred shortly after a steak dinner in which the patient consumed several alcoholic drinks. What is the most likely cause of their symptoms?

Answer 9

gout attack - triggered by red meat/seafood (high purine content) and alcohol (induces purine metabolism via ATP consumption)

Question 10

explain why diuretics could cause secondary gouty arthritis?

Answer 10

uric acid is excreted in kidneys - therefore, anything causing a reduction in GFR would decrease uric acid excretion —> hyperuricemia

ex - renal failure, volume depletion, diuretics

Question 11

explain why myeloproliferative disorders (chronic myeloid leukemia, essential thrombocytopenia, polycythemia vera) can cause secondary gouty arthritis

Answer 11

associated with high cell turnover —> increased purine metabolism —> hyperuricemia —> gout

Question 12

Lesch-Nyhan syndrome

Answer 12

X-linked absence of HGPRT enzyme in purine salvage pathway (hypoxanthine-guanine phosphoribosyltransferase) —> excess uric acid production, causing juvenile gout

presents with neurological impairment + hypotonia/chorea + self-mutilating behavior

Question 13

male child with hypotonia/chorea + self-mutilating behaviors + gout =

Answer 13

Lesch-Nyhan syndrome: X-linked absence of HGPRT enzyme in purine salvage pathway (hypoxanthine-guanine phosphoribosyltransferase) —> excess uric acid production, causing juvenile gout

Question 14

explain how Von Gierke’s Disease can cause secondary gout?

Answer 14

aka glycogen storage disease type 1, glucose-6-phosphate deficiency presenting in infancy

—> severe hypoglycemia, causing seizures and lactic acidosis (Cori cycle)

lactate and urate are linked via URAT1 (urate transporter 1) in kidney —> high lactic acid causes increased uric acid reabsorption —> gout

Question 15

how do gout crystals appear in polarized light microscopy (used for diagnosis)?

Answer 15

gout crystals (needle-shaped) are birefringent - reflect polarized light (waves vibrate in only 1 direction) in 2 ways based on orientation

yeLLow when paraLLel, while blue when perpendicular (think b and p are opposite)

Question 16

how are acute attacks of gout treated? (3)

Answer 16

1. NSAIDs
2. glucocorticoids
3. colchicine

Question 17

what is the mechanism and clinical use of colchicine?

Answer 17

microtubule inhibitor used to treat acute attacks of gout (and also pericarditis, familial mediterranean fever)

binds tubulin and prevents polymerization, inhibiting WBC migration into joints and phagocytosis

Question 18

what kind of drugs are allopurinol and febuxostat, and what is their clinical use?

Answer 18

xanthine oxidase inhibitors (converts hypoxanthine from purines into uric acid) used to prevent gout (also tumor lysis syndrome)

allopurinol - competitive inhibitor
febuxostat - noncompetitive inhibitor

Question 19

why must NSAIDs or colchicine be administered with allopurinol or febuxostat?

Answer 19

these are xanthine oxidase inhibitors that abruptly lower serum uric acid levels (used to treat gout) - this can actually cause precipitation of urate crystals in joints, triggering acute gout attack

NSAIDs/colchicine treat acute gout attacks

Question 20

what is the limiting factor of allopurinol as a first-line drug for gout prevention?

Answer 20

xanthine oxidase inhibitor, but causes severe side effects - GI upset, hepatic toxicity, skin rash (hypersensitivity), rarely bone marrow suppression

[febuxostat can be tried in intolerant patients]

Question 21

which 2 immunosuppressants interact with xanthine oxidase inhibitors (allopurinol, febuxostat)?

Answer 21

azathioprine and 6-MP (mercaptopurine) - both metabolized by xanthine oxidase

if xanthine oxidase is inhibited, effects of these immunosuppressants are boosted, increasing toxicity

Question 22

what is the clinical use of pegloticase?

Answer 22

recombinant porcine uricase (uric acid oxidase, degrades urate) - used to treat severe, refractory gout

given via IV every 2 weeks (attached to PEG/polyethylene glycol, prolongs half life)

[PEGlotICASE = PEG-attached urICASE]

Question 23

what is the mechanism of pegloticase?

Answer 23

recombinant porcine uricase (uric acid oxidase, degrades urate) - used to treat severe, refractory gout

converts uric acid to allantoin, which is more water soluble and can be excreted by the kidneys

[PEGlotICASE = PEG-attached urICASE]

Question 24

what is the clinical use of rasburicase?

Answer 24

Recombinant URICASE (RasbURICASE) - converts uric acid to allantoin (water soluble, excretable)

NOT used to treat gout due to rapid on/off action (more immunogenic) - only used in tumor lysis syndrome when uric acid must be lowered quickly (to prevent acute renal failure due to uric acid nephropathy)

Question 25

contrast the clinical uses of pegloticase and rasburicase

Answer 25

both recombinant uricase (convert uric acid to allantoin)

pegloticase [PEGlotICASE] - attached to PEG (polyethylene glycol) to prolong t1/2, used to treat refractory gout

rasburicase [RasbURICASE] - not attached to PEG, so has rapid on/off action, therefore only used to treat tumor lysis syndrome

Question 26

what is the mechanism and clinical use of probenecid?

Answer 26

blocks PCT reabsorption of uric acid, promoting urate excretion —> can treat gout

note this can also cause uric acid kidney stones by increasing urate in urine

also note it blocks secretion of penicillin in urine, and is a sulfa drug (allergy alert)

Question 27

This drug can treat gout by blocking reabsorption of uric acid at the PCT. It also blocks secretion of penicillin in the urine (originally developed to enhances its effects). This drug is also a sulfa drug, making it an allergy risk. What is?

Answer 27

probenecid

Question 28

contrast the effects of high vs low dose aspirin on uric acid levels (bimodal effect)? why is this important?

Answer 28

high dosages (>2.6grams/day, more than what someone would take) inhibit reabsorption of uric acid (“uricosuric”) —> decrease uric acid levels

low dosages (what would normally be taken) inhibit secretion of uric acid —> increase uric acid levels … therefore, aspirin is not used for pain control in gout!

Question 29

CPPD

Answer 29

Calcium PyroPhosphate Deposition disease: calcium pyrophosphate (2 phosphate linked by O2 atom) deposits in joints, connective tissue

cause unknown, occurs in older patients

Question 30

what are the 3 clinical presentations of CPPD?

Answer 30

Calcium PyroPhosphate Deposition disease - affects joints/connective tissue

1. asymptomatic (chondrocalcinosis found on imaging)
2. acute arthritis (pseudogout, similar to gout)
3. chronic joint disease (similar to osteoarthritis)

Question 31

acute onset of arthritis to the knee can mean 3 things… How can these be differentiated?

Answer 31

differentiated by analysis of synovial fluid

1. gout - uric acid
2. pseudogout (CPPD) - calcium pyrophosphate
3. septic arthritis - WBC, bacteria

Question 32

flares of pseudogout caused by CPPD presenting as acute arthritis are often reported following which type of surgical procedure? why does this make sense?

Answer 32

[Calcium PyroPhosphate Deposition disease]

often following parathyroidectomy - causes calcium levels to fluctuate

Question 33

how does polarized light microscopy differ for gout vs pseudogout (caused by CPPD)?

Answer 33

gout - negatively birefringent, yellow when parallel to light

pseudogout - rhomboid crystals, positively birefringent, blue when parallel

Question 34

what are the 2 reasons for joint pain that occurs in patients with hemochromatosis?

Answer 34

hereditary iron overload

1. iron deposition
2. calcium pyrophosphate deposition (CPPD)