Crystal Flashcards
Gout Manifestations
- Arthritis.
- Tophi (articular, osseous, cartilaginous, or soft tissue).
- Nephropathy
- Stones
Gout RF
- Age, Male, Postmenopausal
- Family history
- Obesity, HTN,
- EtOH, High purine diet,
- Purine metabolism defect,
- CKD, Medullary cystic kidney,
- Meds (low dose ASA, diuretics, cyclosporine)
24h urine uric acid interpretability
- > 800 mg/24 hours suggests overproduction
- <800 mg suggests underexcretion.
ACR recommends NOT checking
and do NOT alkalinize urine
Inherited enzyme abnormalities causing UA overproduction
- Overactivity of phosphoribosylpyrophosphate (PRPP) synthetase.
- Deficiency of hypoxanthine–guanine phosphoribosyltransferase (HGPRT) - partial or complete
- Increased ATP breakdown via: G6PD or Fructose-1-phosphate aldolase deficiency
** Acquired causes of UA overproduction**
- Excess dietary purine (beer, red meat, organ meat, seafood, shellfish, sardines, anchovies)
- Accelerated hepatic ATP degradation (EtOH abuse or fructose ingestion)
- Increased nucleotide turnover (myeloproliferative/lymphoproliferative)
** Foods that lower gout risk **
Cherries
Dairy protein
Vitamin C
?coffee
Low purine/EtOH/fructose diet
Acquired causes of UA underexcretion
- Renal disease, Lead nephropathy (saturnine gout),
- Acidosis (keto-, lactic, respiratory) –> inhib urate secretion
- Drugs
- Hyperparathyroidism,
- Hypothyroidism
** Meds causing decreased UA excretion **
CANT LEAP
CNIs (cyclosporine/tacro)
Alcohol
Nicotinic acid
Thiazides
Lasix (loop diuretics)
Ethambutol
Aspirin (low dose) - DO NOT STOP
Pyrazinamide
Others: levodopa, theophylline, and didanosine
** Uricosuric drugs**
Amlodipine, Losartan,
Atorvastatin, Rosuvastatin,
Fenofibrate (recommended against in Gout guidelines)
ACTH
High-dose salicylates
Leflunomide
EtOH gout mech
Increase hepatic ATP degradation = more urate
Lactate production decreases excretion
Beer has purine guanosine
Acute gout triggers
Diet: purine, fructose, EtOH
Medical illness, eg infxn
Trauma
Dehydration, Exercise
Drugs, Starting ULT, Rads/Chemo
Why is uric acid lvl normal in gout
IL6 → uricosuric effect
Gout Dx
Gold Std: Intra/extracellular MSU crystals in aspirate of synovial fluid/tophi
Gout XR findings
Tophi
Bony erosions - punched out, sclerotic margins, overhanging edes, rat bite erosions
NO juxtaarticular osteopenia
Other imaging modalities and results in gout
US: double contour sign (hyperechoic band of urate crystals on articular cartilage), snowstorm sign
DECT: gout crystals
Tophi locations
Digits - hands/feet
Olecranon bursa
Extensor surface of arm
Achilles tendon
Antihelix of ear
** Medical conditions assocd w/ hyperuricemia**
Obesity
EtOH abuse
Drugs
Psoriasis
Hypothyroid
HyperPTH
DKA
Myeloproliferative, Lymphoproliferative
Hemolytic anemia, PV, SS
Renal insuff, Lead nephropathy,
Medullary cystic kidney dz,
Diabetes insipidus, Bartter’s
Familial juvenile hyperuricemic nephropathy
Reasons gout flares are self limited
- Inflamm → apolipoprot B influx into joint coating crystals and reducing inflamm
- Phagocytosis and neutrophil clearance → less crystals
- Neutrophil extracellular traps (NETs) release protease to digest inflamm mediators
- Heat from inflamm enhance urate solubility
- ACTH secreted from pain suppresses inflammation
- Proinflammatory cytokines (IL1 and TNF) balanced by production of cytokine inhib and regulatory cytokines like TGF-B
** Gout flare pathophysiology **
- MSU crystals recognized by TLR2/4 on chondrocytes and macrophages → NFkB activation and pro-IL1beta
-Macrophages phagycytose crystals activating NLRP3 inflammasome → activates caspase 1 → converts pro-IL1b to active IL1b → IL6, IL8, TNF, PGs, O2 radicals
- MSU activate complement and induce lysosomal enzyme release
- Neutrophils degranulate and NETosis that cause inflammation but also form large “aggNETs” that sequester MSU crystals and form nidus for tophus
** Renal diseases that can cause gout / hyperuricemia**
- Acute uric acid nephropathy: UA in collecting ducts and ureters → ARF (eg TLS)
- Chronic urate nephropathy - UA in renal INTERSTITIAL tissue w/ surrounding giant cell rxn → proteinuria w/o renal dysfcn
- UA Stones (radiolucent)
- Medullary cystic kidney dz
- Lead intox (saturnine gout)
- Familial juvenile hyperuricemic nephropathy
** Indications for ULT**
2 or more flares in a yr
Stones (urate or calcium)
Tophi
Erosions
Mod/Severe CKD (GFR<60)
UA > 565
** How does UA renal transport affect hyperuricemia and examples of drugs that stimulate or inhib it**
URAT1 for REABSORPTION of UA
- Drugs inhib URAT1: probenecid, losartan, high dose salicylate, benzbromarone, lesinurad
- Drugs stimulating URAT1: lactate, low dose ASA, diuretics
** Acute Gout Tx with dose (+contraindications)**
NSAID (CKD, PUD, CHF): Indomethacin 50mg TID, Naproxen 500BID
Colchicine (ELDERLY, renal/hepatic insuff, concomitant 3A4 inhibitors eg grapefruit juice, HAART, cyclosporine, diltiazem, verapamil): 1.2mg then 0.6mg s/p 1h
GC: IA, PO, IM
2nd line:
IL1 inhib (Anakinra, Canakinumab)
ACTH
Allopurinol
- caution in which groups
- what to send for
- what can happen
Han chinese, Korean, Thai
African American
HLA B5801
SJS, fever, hepatitis, renal failure, eosinophilia
**desensitize if can’t take other ULT
** Allopurinol considerations **
Can prevent warfarin metabolism → prolonged clotting time
Mercaptopurine / AZA also metabolized by XO → increased bone marrow toxicity and immunosuppression when used with allopurino/febuxostat
ULT enzyme targets
Allopurinol AND Febuxostat target xanthine oxidase (prevents hypoxanthine to xanthine, and xanthine to UA)
Probenecid targets URAT1 to causing uric acid to be renally secreted
Febuxostat considerations
CVD (CARES trial)
**ULT options and doses **
Allopurinol 50 or 100mg and increase by similar q2-5wks until <6 or <5 if tophi
If fail or contraindication: Febuxostat: 40mg and increase to 80mg after 2-5wks
Pegloticase 8mg q2wks over 2hr
Probenecid 250mg BID x1wk then 500mg BID and increase by 500mg q4w if not at goal
NSAID MoA
Weak organic acid accumulate at inflamed joints w/ low pH
Inhib prostaglandin synthesis via COX inhibition
MAYBE: inhib superoxide formation, degradative enzymes, cytokine production by inhib NFkB, neutrophil aggregation/adhesion
Colchicine MoA
Irrev binds free tubulin dimers to disrupt microtubule polymerization → inhib neutrophil chemotaxis, phagocytosis, and cytokine secretion
Inhib phopholipase A2 → less inflammatory PG and leukotrienes
Modulates pyrin expression
Allopurinol MoA
NONSELECTIVE xanthine oxidase inhibitor preventing hypoxanthine → xanthine → UA
Febuxostat MoA
SELECTIVE xanthine oxidase inhibitor preventing hypoxanthine → xanthine → UA
Uricosuric (probenecid, lesinurad, benzbromarone) MoA
Competitively inhib UA reabsorption at proximal convoluted tubules → more excreted
Inhib excretion of weak organic acids (penicillin, beta lactam)
Pegloticase/Rasburicase MoA
Recombinant urate oxidase enzyme (uricase) converts UA to allantoin (inactive/soluble UA metabolite) → urinary excretion
Pegloticase consideration
G6PD deficiency → Hemolytic anemia, methemoglobinemia
Can cause gout flare
Infusion rxn and anaphylaxis
**Do not use with other ULT
ACTH MoA
Triggers endogenous steroid release from adrenal gland
Activates melanocortin R on macrophages → downreg of immune response
Anakinra MoA
IL1 R ANT - blocks IL1a/b from binding R
Corticosteroid MoA
Binds/activates cytoplasmic GC R’s that bind DNA and lead to gene transcription of anti-inflamm prot and inhib of proinflamm gene transcription
Also binds GC R’s on lymph/monocytes → anti inflamm fx
Contraindications for probenecid
Pt who overproduce UA (24h urine >800mg UA)
G6PD def
GFR<50mL/min
Uric acid stones
Avoid w/ salicylates
Avoid in elderly
Duration of antiinflamm PPX while on ULT
3-6mo
** CPPD RF/disease assoc **
Idiopathic
Joint trauma
Meniscectomy
Genetic (ANKH gene)
HyperPTH
HypoMg/PO4
Hemochromatosis, Wilson’s
Gittleman
Hypothyroid
Amyloid
Hemosiderosis
CPPD crystal formation pathogenesis
High lvls of inorganic pyrophosphate in cartilage via:
- ANKH mutation: transport PP from chondrocyte into cartilage
-ENPP1/3 overactivity → more PP via ATP hydrolysis
-Hypophosphatasia: ALP breaks down PP
-HypoMg: Mg is cofactor for ALP fcn
-Ca (via HyperPTH), iron, and Copper (wilsons) inhib ALP
Enhanced CPP nucleation via:
- Ca (HyperPTH), Fe, copper enhance crystal formation
- Mg inhib nucleation
- OA cartilage composition (osteopontin) facilitate crystal formation
** CPPD classification and presentation**
- Asymptomatic: radiographic w/o sx
- Acute arthritis (Pseudo gout): mono/oligo (MC = knee and TFCC)
- Chronic arthritis (Pseudo RA): poly (MCP/wrists)
- OA w/ CPPD (Pseudo OA): unusual OA joints - MCP, radiocarpal, elbow, shoulder
-OTHER (see other flashcard)
** Other CPPD presentation **
Cspine:
-Stenosis from CPPD of ligamentum flavum and/or transverse ligament
-Crowned dens: CPPD above odontoid (meningismus)
-Pseudotophaceous: periarticular/bony deposition
-Pseudoneuropathic: charcot like on XR w/ normal pain sensation
-Axial involvement: intervertebral disk and SI joint involvement
Crystals involved with chondrocalcinosis
Calcium Pyrophosphate
Basic calcium phosphate
Calcium hydroxyapatite
CPPD vs gout
1st MTP rare
Less painful
Longer to peak intensity
Usually single joint
Resolves within 7-10d
Pathogenesis of pseudogout
Crystals → inflammation via:
- TLR2 in phagocytes and chondrocytes → inflammation
- Interaction with intracellular NLRP3 inflammasome → caspase 1 activation and cytokine IL18, IL1b → TNFa
- Release of NETs
- Interact w/ cell membrane → nonspec activation and release of PG, leukotrienes, cytokines
Microscopy for CPPD
Weakly positive birefringent, blue, rhomboid
vs/ gout: negative birefringent, yellow, needle
Pseudogout triggers
Medical illness eg MI
Surgical procedure
Fluid shifts w/ shift in serum Ca
IA hyaluronate
Lasix
GCSF
IV bisphosphonates
Pseudogout tx
NSAID, colchicine, low dose pred
HCQ, MTX, IL1 ANT
XR differences pseudoOA (CPPD) vs OA
OA: medial knee → varus
CPPD OA: lateral knee → bilateral/unilateral VALGUS; bone spurs and flexion contracture
CPPD workup labs
TSH
PTH
ALP
Ferritin
Ca
Mg
PO4
Cr
Urine copper
Tx for CPP crystals
Mg - inhib crystal nucleation; (HypoMg caused by loop/thiazide diuretics, PPI, CNIs)
Probenecid - lowers PPi by blocking ANKH
** Clinical syndromes assocd w/ BCP crystals / apatite disease **
Calcific periarthritis (deposit on tendons, bursae, joint capsules)
BCP arthropathy (OA, synovitis, destructive arthropathy eg Milwaukee)
Subcutaneous/soft tissue (CTD eg SSc, DM, SLE, MCTD; tumoral calcinosis; metastatic calcification (RF w/ high Ca-PO4 product)
Crystals and particles seen in synovial fluid
Crystals: MSU, CPPD, CaPO4, Ca oxalate,
Cholesterol crystals, lipid droplets
Corticosteroid crystals
Starch from gloves
Metallic fragments from prosthetic joints
Ig crystals in Cryo
Hgb
Aluminum, xanthine, amyloid, cystine
BCP under microscopy
NOT visible under light/polarizing microscopy bc small and lack birefringence
Clumps can be seen with ALIZARIN red staining (not specific and CPP stains + too)
Common tendon affected by calcific periarthritis
Rotator cuff (supraspinatus) bc poor blood flow and Ca builds up
Shoulder, hips
Calcific tendinitis Tx
PT, NSAID
Barbotage (repetitive aspiration/lavage to disrupt calcification)
EDTA (chelates Ca)
High energy extracorporeal shockwave therapy
Pulsed US
Surgical/arthroscopic debridement if large
Hydroxyapatite pseudopodagra
- what is it
- where is it seen
- Ix results
Acute calcific periarthritis of 1st MTP BUT in PREMENOPAUSAL women, NO MSU, and characteristic calcification on XR
Crowned dens syndrome
- pathophys
- clinical manifestation
- imaging findings
Acute calcific periarthritis via CPP or BCP of odontoid process → neck pain, meningismus
CT: calcification surrounding top/sides of dens w/ horseshoe or “crown” like appearance
BCP arthritis Dx
XR showing characteristic calcification
Clumps on microscopy ~ shiny stacked coins
Transmission electron microscopy
Alizarin red (not specific)
Milwaukee shoulder manifestations
Unilateral/Bilateral shoulder pain with use and lying in bed
Restricted/hypermobile from instability
Large joint effusion
Milwaukee shoulder ix
Aspirate: blood tinged w/ low leukocytes (NONINFLAMMATORY)
XR:
- Early: **superior subluxation of humeral head (rotator cuff tear) **
- Late: Sclerosis, cysts, erosions, and destruction of GH joint
Milwaukee shoulder Tx
NSAIDs, PT, Jt protection
Arthrocentesis, Perc jt lavage
IA steroids
Surgery if advanced
** Steroid crystal appearance and presentation **
Small, rectangular, weakly birefringent
+ and - birefringent (BOTH)
Calcium oxalate crystal appearance and presentation
Bipyramidal/envelope shaped
Pt w/ ESRD or oxalosis → bone pain and #
Arthritis/tenosynovitis
NEGATIVE birefringent
Cholesterol crystal appearance and presentation
From chronic joint effusion (eg RA, cholesterols from neutrophil cell membranes)
Square/plate like
NEGATIVE birefringent
No inflamm
Talc/starch appearance and presentation
Small beach ball appearance
Lipid droplet appearance and associated conditions
Maltese cross appearance
May be due to fracture or pancreatitis
** Discuss the inflammasome
- Multimeric protein complexes w/ sensor, adaptor, and zymogen procaspase-1.
- Assembles in response to DAMP/PAMP
- Leads to caspase 1 activation convert pro-IL1b to IL1b and cause pyroptosis
- Implicated sJIA, crystals, FMF, CAPS
2 reasons why MTP involved so commonly involved in GOUT?
-Gout/tophi = predilection for cooler, acral sites (decreased MSU solubility)
-Joints that have undergone degenerative changes provide a nidus for crystal formation (1st MTP OA)
** Why do patients with renal transplant get gout? **
- Anti-rejection medications: Tacro and Cyclosporine increase UA
**List 3 differences in gout in females compared to males? **
- Female develop gout at older age (post menopause)
- Polyarticular attacks more common
- Females often have OA, HTN and mild CKD or are receiving diuretics
- Tophi are common on previously damaged joints, such as Heberden’s nodes and finger pads
**What is Milwaukee shoulder? **
- Severe degenerative arthritis of GH joint with loss of the rotator cuff associated with the presence of basic calcium phosphate crystals.
Describe the production of uric acid.
Nucleotides (GMP, AMP) →
Inosine → (via purine nucleoside phosphyrlase)
Hypoxanthine → (via xanthine oxidase)
Xanthine → (via xanthine oxidase)
Urate
Birefringent crystals
Positive: CPPD
Negative: MSU, cholesterol, calcium oxolate
BOTH: Corticosteroids
NONE: CaPO4 (apatite)
Why does postinjection flare happen
Phagocytosis of corticosteroid crystals cause rupture of synovial fluid leukocytes causing release of inflammatory mediators
If ULT not working
ACR 2020: Change vs adding another uricosuric agent
Change to peglotiase if ongoing tophi and flares despite XOI, uricosurics and other interventions. If no flares or tophi, do NOT switch to pegloticase even if uric acid above target
