gout CPPD (wk5) Flashcards
2 bases are?
pyrimidine (single ring) or purine (double ring)
pyrimidine= CUT
purine= :pure as gold” = AG
what are the bases in DNA vs RNA
ACTG vs ACGU
sugars
5 C ribose (RNA) or deoxyribose (DNA)
nucleoside vs nucleotide
nucloeside= sugar + base
nucleotide= nucleoside + 1-3 phosphates (i.e. ATP)
ine vs dine or sine endings
ine= bases
sine or dine = nucleoside
3 pyridines to know
- cytosine (cytidine)
- thymine (thymidine) (in DNA)
- uracil (uridine) (in RNA)
CUT ACRONYM!
Note “ine” (DNA bases) to “dine” endings (nucleosides)
4 purines to know
pure as gold = AG + 2 more (HX)
- adenine (adenosine)
- guanine (guanosine)
- xanthine (xanthosine)
- hypoxanthine (inosine)
Note “ine” (bases) to “sine” endings (nucleosides)
pathways for pyrimidine vs purine nucleotide synthesis
purine
1. de novo pathway
2. salvage pathway
pyrimidine
1. de novo pathway
what is activated ribose AKA
phosphoribosyl pyrophosphate PRPP
de novo pathway for purine nucleotide biosynthesis
activated ribose (PRPP) + amino acids + ATP +CO2
salvage pathway for purine nucleotide biosynthesis
activated ribose (PRPP) + base
the base comes from diet, cell turnover
3 main steps of de novo synthesis of purines
PRPP –> phosphoribose (via glutamine adding nitrogen) –> IMP
after IMP is made in de novo synthesis of purines what are the 2 next options
make AMP (via GTP)
or
make GMP (via ATP)
reciprocal control in purine de novo synthesis; when ATP is high you
make ??, when GTP is high is make ??
ATP is high you make GMP, when GTP is high is make AMP
why is salvage pathway for purine synthesis needed
- Important to have, as de novo uses lots of energy
- Uses hypoxanthine, guanine, and adenine bases that already exist
–> via diet, cell turnover
what 2 enzymes could be needed in the purine salvage pathway
and what reaction do they catalyze
HGPRT or APRT
Hypoxanthine-guanine phosphoribosyl transferase
(HGPRT)
Adenine phosphoribosyltransferase (APRT)
useed to catalyze the addition of phosphoribose (sugar+P) from
PRPP to:… the prodcut
Hypoxanthine-guanine phosphoribosyl transferase
(HGPRT) is used to make 2 products in purine salvage pathway what are they
hypoxanthine = IMP
guanine = GMP
what are the 2 substrates for the ring in pyrimidine nucleotide synthesis
Carbamoyl phosphate (made from glutamine, ATP, CO2)
▪ Aspartate
Adenine phosphoribosyltransferase (APRT) is used to make 1 product in purine salvage pathway what is it
adenine to make AMP
what is the difference for pyrimidine vs purine nucleotide synthesis
involves making an intermediate pyrimidine ring first, then attaching a ribose-5-P (via PRPP)
▪ Opposite to purines, where the ring is constructed directly on the ribose-5-P
how to make CTP from UMP in pyrimidine nucleotide synthesis
UMP –> UTP via phosphorylating (2x)
UTP –> CTP via adding nitrogen (aminated) via glutamine
how to make dTMP from UMP in pyrimidine nucleotide synthesis
UMP –> UDP (phosphorylated via kinase)
UDP –> dUMP (deoxugenate)
dUMP –> dTMP (methylated vis folate coenzyme)
what removes phosphate from nucleotides to release nucleosides (catabolism)
nucleotidases
what do pyrimidine bases degrade to
▪ Cytosine to uracil and ultimately alanine
(remove sugar to relaase base)
what do purine bases get degraded to
First to xanthine, then uric acid
* Uric acid is eventually excreted in urine
* Elevated levels can lead to hyperuricemia and gout
▪ Conversion of hypoxanthine to xanthine, and xanthine to uric acid, uses the enzyme xanthine oxidase
what enzyme for hypoxanthine –> xanthine –> uric acid
xanthine oxidase
what is gout
- Can be due to underexcretion (most common) or overproduction (less common) of uric acid→ hyperuricemia
- Hyperuricemia can lead to gout
joint inflammation due to deposition of urate crystals
what is gouty arthritis
▪ Deposition of monosodium urate crystals in the joints → immune cells mount an inflammatory response to crystals
* Known as gout (gouty arthritis)
what is chronic topaceous gout
Nodular masses of monosodium urate crystals (tophi) may be deposited in soft tissues
* Known as chronic tophaceous gout
what is urolithiasis
Uric acid stones can form in the kidneys
seen in gout
what enzymes do humans lack that can lead to gout
uricase
- Humans lack uricase, the enzyme responsible for the degradation of uric acid in other mammals
▪ Uric acid is also highly reabsorbed in the urine
▪ Major modifiable risk factors include diets rich in alcohol (beer has quite a few purines) and meat (especially organ meats), asparagus - Non-modifiable include male sex (much more common in guys) and decreased renal excretion
gout etiology
- Increased uric acid production:
▪ Enzyme defects in degradation of uric acid ▪ Rapidly-dividing cancers – i.e. leukemia - Decreased uric acid excretion (in the kidneys) ▪ Idiopathic
▪ Chronic kidney disease
how are urate crystals activated in gout
phagocytosed by macrophages
Urate crystals are phagocytosed by macrophages, activating them
▪ They then release chemokines that attract neutrophils into the joint, found within the synovial fluid
* Neutrophilsmediatejoint inflammation
Complement activation via the alternative pathway also contributes to neutrophil recruitment.
which cytokine is released when inflammasome is activated
IL1
Phagocytosis by macrophages results in activation of the inflammasome
▪ Secretion of IL-1
▪ Further promotes accumulation of neutrophils and macrophages within the joint
* Release cytokines, free radicals, proteases, & arachidonic acid metabolites
what happens in chronic gout
Chronic gout leads to chronic arthritis with joint erosion, chronic inflammation, development
of pannus, and development of tophi
▪ Urate crystals encrust the articular surface of the joint forming deposits in the synovium
▪ Synovium becomes hyperplastic, fibrotic, and thickened with inflammatory cells (ie. pannus formation)
▪ Destruction of underlying cartilage leads to bone erosion
▪ In severe cases a fibrous or bony ankylosis can form, resulting in loss of joint function.
what is a pathognomic hallmark of gout
tophi
- Large, inflammatory bodies that surround
*
areas of crystal deposition - form foreign-body giant cells
- Consist of macrophages and lymphocytes
- Occur in articular cartilage, ligaments, tendons, and bursae
- Can invade joint and surrounding soft tissues or kidneys
- Earlobes, fingertips
which joints does gout effect
1st MTP!!!
- 1st metatarsal-phalangeal joint, insteps, ankles, heels * Knees, wrists, elbows
- Fingers
- Lower limbs are more often affected than upper
–> become more polyarticular if chronic
how long to get chronic topahceous arthritis in gout
12 years
what enzyme is deficient in leech nyhan syndrome
and what does this causes an accumulation of
HGPRT
accumulation of hypoxanthine and guanine
which break down into uric acid
PRPP also accumulate and stimulates production of purine nucleotides which ultimately breakdown into uric acid
leech nyhan syndrome
hyperuricieamia
deficient HGPRT
Hyperuricemia frequently results in urolithiasis and gouty arthritis
psuedogout AKA calcium pyrophosphate crystal deposition disease (CPPD) causes
▪ Some have a genetic component (autosomal dominant)
▪ Can be caused by hyperparathyroidism, hemochromatosis, diabetes, hypothyroidism
▪ Some medications may trigger pseudogout – this is poorly-defined, though
increased with age
what is the pathology of pseudo gout
▪ Crystals deposit in matrix of menisci, connective tissue
of joint
▪ Rupture, eliciting inflammation as macrophages phagocytose the crystals
▪ Recruit neutrophils, which are thought to mediate inflammatory damage
what joint is most effected in psuedogout
knees
clinical presentation of gout
▪ Can be asymptomatic – can mimic osteoarthritis or
rheumatoid arthritis
▪ Asymmetric, can be monoarticular or polyarticular
▪ Commonly affects knees, less common sites are wrists, shoulders, elbows, ankles
▪ Eventually 50% have significant joint damage (affects mobility)
synovial fluid analysis
to distinguish between septic arthritis, gout, pseudogout, hemarthroses and rheumatic joint diseases
do if think have infectious arthritis, flare of crystal arthritis, or
hemarthrosis, mono arthritis, trauma to joint with effusion
- Septic arthritis must be managed urgently
- Hemarthrosis and gout should also be managed (semi-
urgently)
3 C’s of synovial fluid analysis
▪ Crystals – seen under microscopy with gout and pseudogout
▪Cells–redbloodcells? Leukocytes(neutrophilsor lymphocytes)
▪ Culture – any microorganisms growing in there?
which disorder is the only one that is positive for a culture (of microorganisms)
septic arthritis
crystal shape in gout vs psuedogout
gout: birefringent, needle spa[ed
psuedogout: biregringent, cuboidal
anti gout agents
▪ Target the inflammation
* General: Corticosteriods (previous lecture) * Specific to gout: Colchicine
▪ Analgesics
* NSAIDs (ex aspirin) (previous lecture)
▪ Most common treatment
▪ Decrease uric acid production
* Allopurinol
▪ Increase uric acid excretion
* Uricosurics (probenecid and sulfinpyrazone)
what is colchine
corticosteroid for gout
how does colchine drug work
Binds tubulin and prevents microtubule polymerization
so that leukocytes (neutrophils) cant migrate; decrease inflammation
can reduce frequency of attacks
adverse effects of colchine drug
bone marrow depression
and vomit, ab pain, diarrhea
what does Allopurinol do
Decrease uric acid production
what does Uricosurics do
Increase uric acid excretion
what is allopurinol a competitive inhibitor of
xanthine oxidase
Can precipitate an attack of gout at the beginning of therapy –
why?
* As uric acid concentrations go down, crystals start to dissolve and the immune system responds
▪ Typically give aspirin at beginning of allopurinol therapy to reduce pain
uricosurics action
Block tubular reabsorption of uric acid, increasing excretion
