B6-038 Gout & Hyperuricemia Flashcards
the urate crystals present in tophi come from
purine breakdown
[….] is the only biochemical pathway that has urate as the end product
purine breakdown
the conversion of glutamine to glutamate is what type of reaction?
amidation
does amidation occur in purine or pyrimidine synthesis?
both :)
[…] provides the carbon backbones during the de novo synthesis of nucleotide bases
amino acids
synthesis of […] requires vitamin B9
purine bases
PRPP synthase is regulated by
purine and pyrimidine nucleotides (end product inhibition)
UTP inhibits […], which helps build the ring in pyrimidine synthesis
CAD complex
the first step of the salvage of purine bases is
addition of ribose
3 purine bases
hypoxanthine, adenine, guanine
loss of the enzyme HGPRT causes
Lesch-Nyhan syndrome
classic presentation: male child with motor symptoms, self-mutilation, gout
Lesch-Nyhan syndrome
Lesch-Nyhan syndrome is a defect in
purine salvage
causes excess de novo purine synthesis leading to excess uric acid
key enzyme in deoxynucleotide synthesis
ribonucleotide reductase
hydroxyurea and gemcitabine inhibit what enzyme?
ribonucleotide reductase
what enzyme is deficient in SCID?
adenosine deaminase
(involved in purine breakdown)
proper regulation of ribonucleotide reductase results in
the concentration of all four dNTPs in a cell being roughly equivalent
if dCTP is elevated, how might that effect ribonucleotide reductase?
dCTP would allosterically effect RNR resulting in increased production of ADP, UDP, and GDP
**always trying to ensure all four substrates are roughly equal in cell
primary hyperuricemia is caused by
in-born defects
**secondary is unrelated to genetics
in a patient with gout, prevalence of […] correlates with serum and urinary uric acid levels
nephrolithiasis
for the management of gout, the American College of Rheumatology recommends against
vitamin C supplementation
evidence of support for lifestyle/diet recommendations in the management of gout is [high or low]
low
standard of care diagnostic test for gout
synovial fluid aspirate
why do pre-menopausal females have lower serum uric acid levels than males?
estrogen impact activity of renal uric acid transporters
what part of the renal tubule regulates uric acid?
PCT
inhibits xanthine oxidase, directly reducing the production of uric acid
allopurinol
inhibits OAT transporters
probenecid
inhibits URAT1 transporter
lesinurad
inhibits reabsorption of urate from urine [2]
probenecid, lesinurad
inhibits ribonucleotide reductase, preventing the synthesis of deoxyribonucleotides
hydroxyurea
promotes degradation of urate in serum
pegloticase
third line treatment for persistent gout, very expensive
pegloticase
inhibits tubulin polymerization, used to treat inflammatory conditions
colchicine
inhibits de novo pyrimidine base synthesis preventing cell division making it useful in the treatment of rheumatoid disease
leflunomide
**not helpful for gout as it’s for pyrimidine synthesis, not purine
hydroxyurea prevents
deoxyribonucleotide synthesis
allopurinol and febuxostat MOA
purine breakdown
key enzyme in purine breakdown
inhibition of this reduces the production of uric acid
xanthine oxidase
is there strong evidence for managing gout with diet?
no
**despite this, remains “gold standard”. balance QOL with patient goals and evidence
crucial enzyme for synthesis of all nucleotides
PRPP synthetase
**also involved in purine salvage pathway
inhibits dihydrofolate reductase
methotrexate
best treatment for acute nephrolithiasis caused by tumor lysis syndrome
pegloticase
how does an in-born error in G6P cause an elevated risk of hyperuricemia?
glucose-6-phosphate builds up in liver –> shunts into PPP –> produces more nucleotides –> catabolized –> high levels of uric acid
limited in use of treatment of gout due to impact on excretion of other drugs in kidney
probenecid
inhibits reabsorption of uric acid by URAT1 in PCT
lesinurad
**no longer manufactured
recombinant PEGylated-urate oxidase
converts urate to allantoin
pegloticase
drugs for gout that do NOT impact nucleotide metabolism [3]
pegloticase
lesinurad (d/c)
probenecid
inhibit xanthine oxidase to directly reduce uric acid production, specifically treating gout
allopurinol
febuxostat
drugs that inhibit cell division by reducing nucleotide availability
used to treat autoimmune disorder and cancer, not necessarily gout [3]
lefunomide (arthritis)
hydroxyurea (cancer)
methotrexate
transporters in PCT that may be responsible for association of gout and high fructose sodas
GLUT9
“priming” of uric acid reabsorption is dependent on […] loading the PCT cells with anions
sodium
gout is defined as both […] and […]
crystal formation and inflammation
adenosine deaminase deficiency causes
SCID
how does adenosine deaminase deficiency cause SCID?
prevents adenosine breakdown –> adenosine builds up, inhibiting RNR –> reduces dNTP pool –> immune cells are very mitotically active so they are very sensitive to this
unbalanced dNTPs can lead to
ds breaks in DNA
ribonucletotide reductase inhibitors
hydroxyurea, gemcitabine
condition resulting from defective purine salvage
Lesch-Nyhan
can be given prophylactically to help prevent tumor lysis syndrome caused by chemotherapy
allopurinol
converts ribose to PRPP
PRPP synthetase
how does tumor lysis syndrome cause hyperuricemia?
high levels of nucleotide catabolism
gout is caused by the precipitation of [….] crystals in joints
monosodium urate
needle shaped crystals under polarized light
gout
treatment for ACUTE gout [3]
NSAIDs, glucocorticoids, colchicine
preventative treatment for chronic gout [2]
allopurinol
febuxostat
allopurinol and febuxostat competitively inhibit
xanthine oxidase
allopurinol can be used concurrently with chemotherapy to prevent
tumor lysis associated urate nephropathy
allopurinol can increase the concentrations of [2]
azathioprine
6-MP
recombinant uricase catalyzing uric acid to allantion
pegloticase
inhibits reabsorption of uric acid in PCT
probenecid
probenecid can also inhibit the secretion of
penicillin
can precipitate uric acid calculi or lead to sulfa allergies
probenecid
binds and stabilizes tubulin to inhibit microtubule polymerization
colchicine
colchicine inhibits [….], causing impaired neutrophil […] and […]
microtubule polymerization
chemotaxis
degranulation
rate determining enzyme of the HMP shunt
G6PD
rate limiting enzyme of de novo purine synthesis
PRPP
inhibits ribonucleotide reductase
hydroxyurea
inhibits dihydrofolate reductase in humans
methotrexate
lesch-nyhan is caused by
defective purine salvage
one of the major causes of autosomal recessive SCID
adenosine deaminase deficiency
what enzyme is absent in Lesch-Nyhan?
HGPRT
key enzyme in the purine salvage pathway
HGPRT
which pathway operates at a higher rate in children with Lesch-Nyhan?
de novo purine synthesis
leflunomide inhibits [….] synthesis
pyrimidine
medication that inhibits dihydoorotate dehydrogenase
leflunomide
leflunoamide is used to treat
rheumatoid arthritis
