rheumatology 3: crystal arthropathies

Question 1

what is the de novo pathway of purine nucleotide biosynthesis?

Answer 1

The de novo pathway of purine nucleotide biosynthesis is a series of biochemical reactions that synthesize purine nucleotides from simple precursor molecules.
activated ribose (PRPP) + amino acid + ATP + CO2 … –> nucleotide

Question 2

what are the steps in the de novo synthesis pathway of purines

Answer 2

1. glutamine is used to transfer an N to PRPP –> results in a phosphoribose (sugar + P) with an added N
2. base is built on this N
3. the nucleotide product is inosine monophosphate (IMP)
4. IMP can then be used to make AMP or GMP (GTP to make AMP and ATP to make GMP)

Question 3

what is the salvage pathway of purine synthesis?

Answer 3

alternative pathway because de novo takes too much energy
uses pre-existing hypoxanthine, guanine, and adenine bases

Question 4

what are the enzymes involved in the salvage pathway?

Answer 4

1. hypoxanthine-guanine phosphoribosyl transferase (HGPRT) –> catalyzes the addition of phosphoribose (sugar + P) from PRPP to: hypoxanthine to make IMP & guanine to make GMP
2. adenine phosphoribosyltransferase (APRT) catalyzes the addition of phosphoribose (sugar + P) from PRPP to adenine to make AMP

Question 5

what is pyrimidine nucleotide synthesis?

Answer 5

de novo pathway: makes an intermediate pyrimidine ring first, then attaches a ribose-5-P (via PRPP)

Question 6

what are the substrates for the rings?

Answer 6

carbamoyl phosphate (made of glutamine, ATP, CO2), and aspartate

Question 7

what is the catabolism of nucleotides?

Answer 7

nucleotidases remove P from nucleotides to release nucleosides
sugar removed to release bases –> pyrimidine bases degraded –> cytosine to uracil to alanine
purines bases degraded –> degraded to xanthine then to uric acid (excreted in urine)
–> elevated levels lead to hyperuricemia and gout

Question 8

what is gout a result of?

Answer 8

can be due to underexcretion (common) or overproduction (less common) of uric acid –> hyperuricemia –> gout

Question 9

how does hyperuricemia lead to gout?

Answer 9

deposition of monosodium urate crystals in the joints –> immune cells mount an inflammatory response to crystals (gouty arthritis)
nodular masses of monosodium urate crystal (tophi) may be deposited in soft tissue (chronic tophaceous gout)
uric acid stones can form in the kidneys (urolithiasis)

Question 10

can humans degrade uric acid?

Answer 10

no, because humans lack uricase (the enzyme responsible for degradation of uric acid)

Question 11

what is the epidemiology of gout?

Answer 11

10-20% of the population has hyperuricemia but not all develop gout (1-4%)

Question 12

what is the etiology of gout?

Answer 12

increased uric acid production: enzyme degradation of uric acid & rapidly dividing cancers
decreased uric acid excretion in the kidneys: idiopathic and chronic kidney disease

Question 13

what is pathophysiology of acute grout?

Answer 13

monosodium urate crystal precipitation results in acute gouty arthritis
urate crystals are phagocytosed by macrophages activating them –> they release chemokines that attract neutrophils into the joint within synovial fluid
complement activation via alternative pathway also contributes to neutrophil recruitment
phagocytosis by macrophages result in activation of the inflammasome –> secretion of IL-1 –> more neutrophils and macrophages recruit to joint –> release of cytokines, free radicles, proteases, arachidonic acid metabolites
spontaneous remission within days to weeks

Question 14

what is the pathophysiology of chronic gout?

Answer 14

chronic gout leads to chronic arthritis with joint erosion, chronic inflammation, development of pannus, and tophi
urate crystals encrust articular surface of joint –> deposits in synovium –> synovium becomes hyperplastic, fibrotic, thickened with inflammatory cells –>destruction of underlying cartilage –> bone erosion
fibrous or bony ankylosis can form in severe cases

Question 15

what is tophi?

Answer 15

pathognomonic hallmark of gout
- large, inflammatory bodies that surround areas of crystal deposition
- form foreign body giant cells
-consists of macrophages and lymphocytes
- occur in articular cartilage, ligaments, tendons, and bursae
- can invade joint and surrounding soft tissue or kidneys (can result in renal complications –> urate nephropathy)

Question 16

what is the clinical presentation of acute gout?

Answer 16

acute attacks in: 1st metatarsal-phalangeal joint, instep, ankles, heels, knees, wrists, elbows, fingers (lower limbs are affected more)
very painful, inflamed joints

Question 17

what is the clinical presentation of chronic gout?

Answer 17

attacks recur in shorter intervals and frequency becomes polyarticular –> disabling chronic tophaceous gout develops

Question 18

what happens when there us a deficiency of HGPRT?

Answer 18

HGPRT stands for Hypoxanthine-Guanine Phosphoribosyltransferase. It is an enzyme that plays a crucial role in the purine salvage pathway of purines. HGPRT catalyzes the conversion of hypoxanthine and guanine to their respective monophosphate forms (IMP & GMP). As a result, there is an accumulation of purine metabolites, including hypoxanthine and guanine. These accumulated purines are then converted to uric acid, leading to hyperuricemia –> LESCH- NYHAN SYNDROME

Question 19

what does hyperuricemia result to?

Answer 19

urolithiasis (kidney stones) and gouty arthritis and severe neurological problems

Question 20

what is CPPD?

Answer 20

• calcium pyrophosphate deposition disease (CPPD)
• aka pseudogout

Question 21

what is the epidemiology of CPPD?

Answer 21

common, chances increase with age

Question 22

what is the etiology of CPPD?

Answer 22

most cases are sporadic
may be genetic (autosomal dominant)
can be caused by hyperparathyroidism, hemochromatosis, diabetes, hypothyroidism
can be triggered by medications

Question 23

explain the pathology of CPPD

Answer 23

• 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

Question 24

how does CPPD present?

Answer 24

• can mimic osteoarthritis or rheumatoid arthritis
• asymmetric, monoarticular or polyarticular
• affects knees, less common in wrists, shoulders, elbows, ankles
• –> 50% have significant joint damage

Question 25

what is the treatment for CPPD?

Answer 25

no therapy to prevent damage –> symptomatic treatment

Question 26

what is synovial fluid analysis?

Answer 26

a test to distinguish between different DDX (septic arthritis, gout, CPPD, hemarthrosis, rheumatic JD)
good at distinguishing bw acute gout or pseudogout and septic arthritis

Question 27

when is synovial fluid analyses done?

Answer 27

• when you suspect septic arthritis, flare of crystal arthritis, hemarthrosis
• monoarthritis with no prior history
• trauma to a joint with effusion
• 3 C’s
  -crystals (seen in gout and pseudogout)
  
  • cells- RBCs, leukocytes (neutrophils or lymphocytes) –> raised in SA, hemarthrosis
  • culture: for microorganisms (would be positive for SA)

Question 28

what do the crystals in gout and pseudogout look like?

Answer 28

gout: birefringent, needle shaped
CPPD: non- birefringent, cuboidal

Question 29

what are therapies for gout?

Answer 29

to target inflammation: corticosteroids (colchicine)
analgesics: NSAIDs
decrease uric acid production: allopurinol
increase uric acid excretion: uricosurics (probenecid and sulfinpyrazone)

Question 30

what is the mechanism for colchicine?

Answer 30

binds tubulin and prevents microtubule polymerization
can reduce frequency of attacks and can also terminate it if taken at first sign of attack

Question 30

what are side effects of colchicine?

Answer 30

bone marrow depression
less serious: nausea, abdominal pain, diarrhea

Question 31

how does allopurinol work?

Answer 31

competitive inhibitor of xanthine oxidase
can precipitate an attack of gout in the start
–> Xanthine oxidase is an enzyme involved in the conversion of purines into uric acid. By inhibiting this enzyme, allopurinol reduces the production of uric acid.
is used preventatively

Question 32

how do uricosurics work?

Answer 32

blocks tubular reabsorption of uric acid –> increases excretion