2: Crystal Induced Arthropathies Flashcards
what are four microcrystals associated with crystal induced arthropathies?
- monosodium urate (MSU)
- calcium pyrophosphate dihydrate (CPPD)
- calcium apatite (apatite)
- calcium oxalate (CaOx)
what conditions are included in a ddx for crystal induced arthropathies?
- gout
- pseudogout: acute CPP crystal arthritis
- psoriatic arthritis
- reactive arthritis
- osteoarthritis
- rheumatoid arthritis
- septic arthritis
- cellulitis
pathogenesis of gout
Hyperuricemia followed by extracellular deposition of uric acid crystals in synovia of joints, bursae, and/or tendons - then release of crystals into joint or bursae with accompanying inflammation (key involvement of IL-1)
biochem associated with gout
- uric acid = end product of human purine metabolism
- humans cannot metabolize it- must be excreted
- serum [urate] determined by balance of urate production vs. elimination
definition of hyperuricemia
> 6.8 mg/dl (limit of its solubility in serum)
at this level, there is an accumulation of MSU at levels that drive the precipitation of urate crystals
some famous people with gout
- King Henry VIII
- Ben Franklin
- Jared Leto
- Ansel Adams
- Maurice Cheeks
risk factors for gout
- age
- male; or PMS women
- HTN (thiazide diuretic use)
- obesity
- hyperlipidemia
- hyperuricemia
- dietary excess: meat, seafood, alcohol (highest with beer)
- dehydration
- trauma/surgery/transplant
- AMI/stroke
- urate lowering therapy
- Lesch-Nyhan syndrome (HGPRT def: orange, sandy urine; self mutilation, mental retardation)
causes of hyperuricemia
- 90% secondary to underexcretion
- 10% secondary to overproduction
use 24h quantitative urine uric acid to help define pathophysiology (normal = 250-750mg/24h)
4 causes of primary uric acid overproduction
- Lesch Nyhan (NGPRT deficiency)
- overactive PRPP
- G6PD deficiency
- F1P aldolase deficiency
many causes of secondary uric acid overproduction
- myelo/lympho-proliferative disorders
- malignancies
- hemolytic diseases
- psoriasis
- obesity
- chemotherapy (tumor lysis)
- Down syndrome
- Glycogen storage disease (III, V, VII)
- excessive purine or fructose rich foods
- pancreatic extract, Nicotinic acid, B12 deficiency
- alcohol (mix of overproduction and underexcretion)
relationship b/w hyperuricemia and alcohol
- alcohol needs ATP degradation to metabolize thus increased purine turnover and urate generation (overproduction)
- binging can cause elevated lactate levels and decreased renal excretion via URAT-1 (underexcretion)
- promotes diuresis via suppression of ADH causing dehydration, volume depletion, and urate retention (underexcretion)
what alcohols affect purine levels?
beer, ale, and distilled spirits
wine does not!
describe urate excretion
kidney:
1. glomerular filtration of all serum urate
2. PCT resorption of 99% filtered load
3. resecretion in descending of 50% resorbed load
4. resorption in ascending of 80% of resecreted load
5. excretion of about 10% of filtered load (about 600 mgms/d)
primary causes of renal underexcretion
- hereditary deficiency in urate exporter
- medullary cystic kidney disease in kids
secondary causes of renal underexcretion
- kidney disease
- lactic and diabetic or starvation ketoacidosis
- dehydration: fluid loss, heart failure
- hypoparathyroidism
- hypothyroidism
- sarcoidosis
- pre-eclampsia
- medications
drugs that promote hyperuricemia
- diuretics: thiazide > loop
- organic acids: low dose salicylates, nicotinic acid, pyrazinamide
- cyclosporine
- ethambutol
- ethanol
- levadopa
- CSF?
- lead toxicity (lead nephropathy -> saturnine gout)
- laxative abuse (alkalosis)
- severe salt restriction
presentation of acute gouty arthritis
- acute inflammation with pain, redness, and swelling
- max severity in hours, resolves in 3-10d
- 80% monoarticular, often podagra (great toe MTP)
- pain to even put sheet over foot
- inflammation can spread beyond joint, giving tenosynovitis mimicking cellulitis
- urate crystals in synovial fluid at time of inflammation
diagnosis of acute gouty arthritis
- joint aspiration (hyperuricemia + joint effusion not enough)
- look at fluid under polarized light
- can mimic septic arthritis (fever, leukocytosis, high ESR)
what imaging can be used to tentatively diagnose gout, and what will you see?
US - superficial, hyperechoic, irregular band on surface of articular cartilage = “double contour sign” or “urate icing”
MRI/ CT - good for finding gouty erosions
most important indication for arthrocentesis
to check for septic arthritis
how can you determine if blood in aspirated synovial fluid is from hemarthrosis or from trauma from a poorly performed arthrocentesis?
- trauma: blood may remain unmixed with synovial fluid, appearing as red streaks in an otherwise yellow fluid
- hemarthrosis: synovial fluid is generally homogeneously bloody and does not form a clot
how to differentiate MSU from CPPD crystals with polarized microscopy
MSU: yellow parallel, blue perpendicular
CPPD: blue parallel, yellow perpendicular
how long can asymptomatic hyperuricemia last
up to 20 years
3 stages of gout
- acute gout
- intercritical gout
- chronic tophaceous gout
describe the first gout attack
- usually monoarticular (big toe, instep, ankle, heel, knee, wrists, fingers, elbows)
- can get bursitis, tendinitis and tenosynovitis
- acute w/ intense pain and limited time
- men 40-60 y/o and women more than 60 y/o
describe intercritical gout
- after 1st attack there is “intercritical gout period”
- most untreated patients will have a second episode within 2 years
- trend if untreated:
- additional acute attacks
- progressively shorter asymptomatic periods
- increasingly severe, prolonged and polyarticular flares
describe chronic recurrent gout
- polyarticular acute exacerbations
- more commonly in upper extremities
- bony erosions and deformities
tophaceous gout
- solid urate deposits (tophi) in tissues
- 75% with tophi after 20 years of untreated gout
factors that can precipitate a gout flare
- trauma
- surgery or hospital admission w/ IV fluids
- starvation
- dehydration
- increased alcohol consumption (but NOT wine)
- dietary indulgence
- acute changes in serum uric acid level
- stopping or starting medications for gout
gout treatment goals
- rapidly end acute flares
- protect against future flares for lifetime
- reduce change of crystal inflammation
- prevent disease progression (lower serum urate to less than 6 mg/dl)
- correct metabolic cause
specific treatments for acute gout
- rest, ice packs, elevation
- increase water consumption
- NSAIDs
- colchicine
- glucocorticoids
- IL-1B antagonists
does ending acute flares cure gout?
no- but it controls inflammation, relieves pain. but not a cure b/c crystals remain in joints
what steps can one take after a first attack to try to slow down/prevent future attacks?
- avoid dehydration
- modify meds
- reduce alcohol intake
- lose weight
- meds to increase excretion (probenecid)
- meds to reduce production (allopurinol, febuxostat, PEG-uricase)
- prophylaxis against attacks with colchicine and NSAIDs
reasons to start urate lowering therapy
- recurrent attacks
- urate nephrolithiasis
- tophaceous gout
- evidence of gout-induced joint damage
how do you choose what urate lowering therapy to use
base choice on whether pt is an overproducer or underexcreter:
700/24h = overproducer (10%) - use xanthine oxiase inhibitor
function of uricosuric agents
-increase secretion of urate into urine
examples of uricosuric agents
- probenecid
- benzbromarone
- losartan or fenofibrate (mild urisocurics)
two xanthine oxidase inhibitors and their MOA
- allopurinol: blocks conversion of hypoxanthine to uric acid
- febuxostat (didn’t say MOA)
function of urate oxidase (UO)
catalyzes the oxidation of uric acid to 5-hydroxyisourate, which can then be converted to more soluble and excretable allantoin
(humans have a gene for this, but its non-functional)
calcium crystal disease involves what two crystal types
calcium pyrophosphate dihydrate (CPPD)
basic calcium phosphate (BCP)
describe CPPD disease
- excessive cartilage pyrophosphate production leads to CPPD crystals depositing in joint articular cartilage (hyaline), fibrocartilage (menisci), and ligaments
- can be asymptomatic
- acute release of CPPD crystals into joint space - phagocytosis by macrophages - release of chemotactic and inflammatory substances - activating inflammasome
- can also cause mild chronic inflammation
XR diagnosis for CPPD disease
chondrocalcinosis - calcification of the cartilage and fibrocartilage
*high res US helpful b/c XR of CPPD not always detectable
describe the production of CPPD
- extracellular ATP ‘scavenging’ by nucleoside triphosphate pyrophosphate hydrolase yields PP
- OA cartilage matrix abnormal: favors Ca + PP deposition
epidemiology of CPPD
- both sexes equally affected
- idiopathic with aging most common
causes of CPPD deposition
- idiopathic with aging most common**
- complication of primary osteoarthritis
- long term consequence from trauma/menisectomy
- familial chondrocalcinosis
- gitelman syndrome
- systemic metabolic disease (primary hyperparathyroidism)
describe gitelman syndrome
autosomal recessive renal tubular disorder
- mimics chronic thiazide ingestion
- presents as older child/adult w/ hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and normal BP
- leg and arm cramps, weakness, polyuria, nocturia, and chondrocalcinosis
three possible presentations of CPPD disease
- asymptomatic CPPD crystal deposition
- acute CPP crystal arthritis (pseudogout)
- chronic CPP crystal inflammatory arthritis
describe pseudogout
- acute inflammatory mono or oligoarticular arthritis
- typically involves larger joints (knees most)
- lasts 1-3w
- flares after parathyroidectomy
describe chronic CPP crystal inflammatory arthritis
- pseudo-RA
- non-erosive, asynchronous, inflammatory arthritis with CPPD crystals in joint fluid of clinical joints, suggesting RA
- XR changes more typical of osteoarthritis than RA
MSU vs. CPPD crystals
MSU:
- gout
- needle-shaped, about size of PMN
- negatively birefringent (yellow parallel)
CPPD:
- pseudogout
- rhomboid, smaller than PMN
- positively birefringent (blue parallel)
how does aspirated fluid in CPPD differ from gout
fluid tends to be inflammatory - typically 15,000 to 30,000 WBCs (90% neutrophils)
XR findings of CPPD
- chondrocalcinosis
- subchondral cysts
- beak-like projections (2nd and 3rd metacarpal heads)
how an you diagnose CPPD when unable to prove crystals?
high res US:
- thin hyperechoic bands, parallel to surface of cartilage (knee)
- ‘punctate’ pattern w/ several thin hyperechoic spots (fibrous cartilage and tendons)
- homogenous hyperechoic nodular or oval deposits in bursae and articular recesses
treatment of pseudogout
- joint aspiration and intra-articular corticosteroid
- NSAIDs
- colchicine
- systemic corticosteroid
pseudogout prophylaxis
- necessary if more than 3 episodes/year
- low dose colchicine
- methotrexate or hydroxychloroquine for refractory chronic inflammation/synovitis
- IL-1B inhibitors for recurrent acute or severe attacks
describe BCP deposition
- closely tied to osteoarthritis
- can cause chondrocalcinosis on XR
- rarely causes acute inflammation- more of a chronic low grade destructive arthritis
what conditions can BCP be found in?
- advanced chronic renal failure (hyperphosphatemia)
- hypercalcemic metastatic calcification
- hyperparathyroidism
- areas of tissue damage (dystrophic calcification)
what is the most common BCP crystal
hydroxyapatite
-primary mineral in bone/teeth (apatite is)
ID of hydroxyapatite crystals in BCP
- amorphous crystals not visible with polarized light*
- if in a clump, edge can be birefringent
- synovial fluid crystal stain w/ alizarin red to ID crystals
- absolute ID with EM
what does hydroxyapatite crystals cause
- cartilage and bone damage with chronic low grade inflammation
- synovial fluid WBC counts less than 2000
presentation of hydroxyapatite crystals
- associated with periarthritis, tendon calcifications
- knees, shoulders, hips, fingers
- acute onset pain and swelling or chronic low grade inflammation
what are hydroxyapatite crystals associated with?
- progressive rotatoe cuff degeneration
- elderly women: Milwaukee shoulder
- extremely destructive chronic arthropathy
- hemorrhagic shoulder effusions
- synovial fluid shows BCP crystals
treatment of BCP crystal deposition arthropathy
- NSAIDs or COX2 inhibitors
- intra-articular or periarticular corticosteroid injections
- local irrigation
- high frequency therapeutic US to degrade BCP crystal deposits
- agents to lower serum [phosphate] may lead to resorption of deposits in renal failure patients receiving hemodialysis
describe primary calcium oxalate deposition disease
- rare hereditary metabolic enzyme defect
- overproduction of oxalic acid
- oxalate crystals in tissue, nephrocalcinosis
- renal failure and death before age 20
describe secondary calcium oxalate deposition disease
- more common than primary
- metabolic abnormality complicating end-stage renal disease dependent on long-term peritoneal/hemodialysis who received ascorbic acid supplements
where do you find CaOx deposits?
- bone, articular cartilage, synovium, and periarticular tissues
- crystals may be shed, causing acute synovitis stimulating synovial cell proliferation and enzyme release, resulting in progressive articular destruction
- deposits in fingers, wrists, elbows, knees, ankles, feet
describe shape of CaOx crystals
- variable shape and variable birefringent to polarized light
- most easily recognizable ones are bipyramidal with strong birefringence and stain with alizarin red
treatment of CaOx arthropathy
- NSAIDs
- colchicine
- intra-articular glucocorticoids
- increased frequency of dialysis (only slight improvement)
- primary oxalosis, liver transplantation
