Calcium containing crystalsCalcium containing crystals

Major manifestationsMajor manifestationsAcute periarthritisAcute periarthritisDestructive arthropathyDestructive arthropathyTissue deposits mimicking tumor like massesTissue deposits mimicking tumor like masses

Types of crystalsTypes of crystalsCalcium pyrophosphate dihydrateCalcium pyrophosphate dihydrateBasic calcium phosphateBasic calcium phosphate

CPPDCPPD

Chondrocalcinosis Chondrocalcinosis Pyrophosphate arthropathy Pyrophosphate arthropathy

CPPDCPPD

Precipitation of crystals of calcium Precipitation of crystals of calcium pyrophosphate dihydrate (CPPD) in pyrophosphate dihydrate (CPPD) in connective tissuesconnective tissues

Ca2P207.2H20Ca2P207.2H20CPPD formation appears restricted CPPD formation appears restricted

principally to fibro- and hyaline cartilage, principally to fibro- and hyaline cartilage, less commonly capsule or tendon less commonly capsule or tendon

EPIDEMIOLOGY EPIDEMIOLOGY

Chondrocalcinosis increases with age Chondrocalcinosis increases with age from the from the 6th decade6th decade and shows and shows femalefemale preponderance . preponderance .

The strong association with The strong association with osteoarthritis (OA)osteoarthritis (OA) and and Joint traumaJoint trauma and and agingaging

PREVALENCEPREVALENCE

65 to 74 years old— 15 percent 65 to 74 years old— 15 percent 75 to 84 years old — 36 percent 75 to 84 years old — 36 percent >84 years old— almost 50 percent >84 years old— almost 50 percent

NTPPPH = Nucleoside triphosphate NTPPPH = Nucleoside triphosphate pyrophosphohydrolasepyrophosphohydrolase

NTPase = ( one kind of NTPPPH) is a NTPase = ( one kind of NTPPPH) is a ectoenzymeectoenzyme

NTP PPi CCPD NTP PPi CCPD productionproduction

(ATP)

NTPaseNTPPPH supersaturation

Metabolism of PPi and formation of CPPD crystals in haemochromatosis (1) and hypomagnesaemia (2).

Wright G D , Doherty M Ann Rheum Dis 1997;56:586-588

©1997 by BMJ Publishing Group Ltd and European League Against Rheumatism

Crystal formationCrystal formation Crystal formation may reflect elevated levels of Crystal formation may reflect elevated levels of

either either calciumcalcium or or pyrophosphatpyrophosphatee (PPi), (PPi), matrixmatrix changeschanges that enhance local CaPPi that enhance local CaPPi supersaturation, supersaturation, NTPPPH overactivityNTPPPH overactivity or a or a combination of these factors. combination of these factors.

A close association is reported with hypertrophic A close association is reported with hypertrophic or metaplastic chondrocytes, the surrounding or metaplastic chondrocytes, the surrounding matrixmatrix often being proteoglycan depleted and often being proteoglycan depleted and degenerative. degenerative.

Site of crystal formationSite of crystal formation

CPPD crystals form in peri-cellular sites,in CPPD crystals form in peri-cellular sites,in the mid-zone of fibro- and hyaline the mid-zone of fibro- and hyaline cartilagecartilage

Inhibitor of CPPD depositionInhibitor of CPPD deposition

Local MgLocal MgProteoglycanProteoglycanAlkalinphosphatase Alkalinphosphatase 5´ nucleotidase5´ nucleotidase

Promoting factor for crystal Promoting factor for crystal formationformation

IronIronCalciumCalciumPhospholipidPhospholipidCopperCopperPTH promotion of PP synthtesisPTH promotion of PP synthtesisOther crystalsOther crystals

Metabolic diseases predisposing to Metabolic diseases predisposing to CPPDCPPD

DefiniteDefinite HyperparathyroidismHyperparathyroidism Haemochromatosis Haemochromatosis HypophosphatasiaHypophosphatasia HypomagnesaemiaHypomagnesaemia Wilson's diseaseWilson's disease HypothyroidismHypothyroidism

ProbableProbable GoutGout Ochronosis Ochronosis joint injection of joint injection of

hyaluronate hyaluronate X-linked X-linked

hypophosphatemic hypophosphatemic ricketsrickets

familial hypocalciuric familial hypocalciuric hypercalcemia hypercalcemia

Clinical manifestationsClinical manifestations

Acute pseudo-goutAcute pseudo-goutMay rarely present asMay rarely present as

Pseudo-rheumatoidPseudo-rheumatoidPseudo-ankylosing spondylitisPseudo-ankylosing spondylitisPseudo-neuropathic arthropathyPseudo-neuropathic arthropathy

Secondary osteoarthritisSecondary osteoarthritisChondrocalcinosisChondrocalcinosisTenosynovitisTenosynovitis

Acute peudogoutAcute peudogout

CPPD crystal induced synovitis – clinically CPPD crystal induced synovitis – clinically resembles goutresembles gout

Precipitated by trauma, surgery or severe Precipitated by trauma, surgery or severe medical illnessmedical illness

Acute attacks are usually self-limiting and Acute attacks are usually self-limiting and resolve within one to three weeks resolve within one to three weeks

Fever is common, mildly confusedFever is common, mildly confused Knee – most common jointKnee – most common joint Coexistence of urate and CPPD crystals in a Coexistence of urate and CPPD crystals in a

single inflammatory effusion is not uncommonsingle inflammatory effusion is not uncommon

Acute CPPDAcute CPPD

Acute pseudogout Acute pseudogout

CPPD crystalsCPPD crystals

Detected by compensated polarized light Detected by compensated polarized light microscopymicroscopyPositively (but weakly) birefringentPositively (but weakly) birefringentRhomboid shapedRhomboid shapedMore difficult to detectMore difficult to detectSmaller and more polymorphicSmaller and more polymorphic

A faintly yellow, positively birefringent, rhomboidal, intracellular crystal characteristic of calcium pyrophosphate dihydrate (CPPD) is seen in the

synovial fluid of a patient with pseudogout, when viewed with compensated, polarized microscopy.

CPPD crystal CPPD crystal

triggers of acute pseudogouttriggers of acute pseudogout

TraumaTrauma Intercurrent medical illnessIntercurrent medical illnessSurgerySurgeryBlood transfusion/parenteral fluid Blood transfusion/parenteral fluid

administrationadministration

AutoremissionAutoremission

PhagocytosisPhagocytosis and dissolution of crystals and dissolution of crystals may play a role. may play a role.

Adhesion of components of Adhesion of components of extracellular extracellular fluid or plasma to crystals may decrease fluid or plasma to crystals may decrease their inflammatory potential. their inflammatory potential.

Familial ChondrocalcinosisFamilial Chondrocalcinosis

Autosomal dominant diseaseAutosomal dominant disease

Clinical disease occurs early in lifeClinical disease occurs early in life

Associated with ANKH gene mutationAssociated with ANKH gene mutationTransmembrane protein involved in Transmembrane protein involved in

pyrophosphate transportpyrophosphate transport

Chronic pyrophosphate arthropathyChronic pyrophosphate arthropathy elderly and female.elderly and female. Asymptomatic radiographic finding of Asymptomatic radiographic finding of

calcification of articular or fibrocartilage.calcification of articular or fibrocartilage.

Charactristic site of CPPD depositionCharactristic site of CPPD deposition

¤ Lateral & medial meninscus in knee jointLateral & medial meninscus in knee joint

((most commonmost common))

¤ Acetabular labrum in hipAcetabular labrum in hip

¤ Fibrocartilageinous Symphysis pubisFibrocartilageinous Symphysis pubis

¤ articular disc of wristarticular disc of wrist

¤ Anulus fibrous of intervertebral discsAnulus fibrous of intervertebral discs

X Ray findingX Ray finding

Normal wristNormal wrist

Axial presentations Axial presentations

'pseudo-ankylosing spondylitis' 'pseudo-ankylosing spondylitis' acute self-limiting meningitic episodes may acute self-limiting meningitic episodes may

relate to CPPD deposition in degenerative relate to CPPD deposition in degenerative ligamenta flava and cervical discsligamenta flava and cervical discs

SpineSpine

Crowned dens syndrome Crowned dens syndrome

Odontoid erosion Odontoid erosion

Pseudo - osteoarthritisPseudo - osteoarthritis

Consider CPPD Consider CPPD disease when O.A disease when O.A occurs in joints not occurs in joints not commonly affected in commonly affected in primary O.Aprimary O.A

Wrist, MCP joints, Wrist, MCP joints, shoulders and elbowsshoulders and elbows

CPPDCPPD

CPPDCPPD

Chronic pyrophosphate arthropathy Chronic pyrophosphate arthropathy DD with OADD with OA

the site of predominant involvement the site of predominant involvement (wrists, shoulders, ankles and elbows are (wrists, shoulders, ankles and elbows are uncommonly affected in OA) uncommonly affected in OA)

the often marked inflammatory component the often marked inflammatory component superimposition of acute attacks superimposition of acute attacks

CPPD disease treatmentCPPD disease treatment

Acute pseudo-goutAcute pseudo-goutNSAIDs , colchicine, I.A steroid injectionNSAIDs , colchicine, I.A steroid injectionProphylaxis with colchicine 0.6mg P.O bidProphylaxis with colchicine 0.6mg P.O bid

Chronic and progressive CPPD crystal Chronic and progressive CPPD crystal depositiondepositionNo effective treatmentNo effective treatmentProbenecid is being investigatedProbenecid is being investigated

Basic calcium phosphate Basic calcium phosphate crystalscrystals

Types of crytalsTypes of crytals HydroxyapatiteHydroxyapatite Tricalcium phosphateTricalcium phosphate Octacalcium phosphateOctacalcium phosphate

Identification of crystalsIdentification of crystals Very difficult to detect secondary to small sizeVery difficult to detect secondary to small size Non-birefringent chunksNon-birefringent chunks Stain positive with Alizarin red stainStain positive with Alizarin red stain

BCP crystal deposition diseaseBCP crystal deposition disease

Acute calcific periarthritisAcute calcific periarthritisDestructive arthropathyDestructive arthropathyOsteoarthritisOsteoarthritisSoft tissue calcificationSoft tissue calcification

Acute calcific periarthritisAcute calcific periarthritis

Hydroxyapatite Hydroxyapatite

Hydroxyapatite Hydroxyapatite

HydroxyapatiteHydroxyapatite

Hydroxyapatite Hydroxyapatite

Destructive arthropathyDestructive arthropathy

Milwaukee shoulder syndromeMilwaukee shoulder syndromeBCP crystal associated joint degenerationBCP crystal associated joint degenerationMassive joint effusions – usually bloodyMassive joint effusions – usually bloodyMay effect other joints – knees, hips and May effect other joints – knees, hips and

elbowselbows

Milwaukee shoulder Milwaukee shoulder

BCP crystals and OABCP crystals and OA

Calcium crystals are very common in O.A Calcium crystals are very common in O.A joints ( in contrast rarely found in R.A )joints ( in contrast rarely found in R.A )

Data support a causative roleData support a causative rolePresence correlates strongly with severity of Presence correlates strongly with severity of

radiographic O.Aradiographic O.A

BCP crystal deposition in other BCP crystal deposition in other diseasedisease

AtherosclerosisAtherosclerosisHydroxyapatite is the major constituentHydroxyapatite is the major constituentPositive correlation between coronary artery Positive correlation between coronary artery

calcification and cardiovascular eventscalcification and cardiovascular eventsBreast cancerBreast cancer

Mammary microcalcifications is a diagnostic Mammary microcalcifications is a diagnostic marker of breast cancermarker of breast cancer

BCP crystals augment mitogenesis in breast BCP crystals augment mitogenesis in breast cancer cell linescancer cell lines

Potential treatment optionsPotential treatment options

PhosphocitratePhosphocitrate Inhibits BCP and CPPD crystal formationInhibits BCP and CPPD crystal formationBlocks degeneration promoting effects of Blocks degeneration promoting effects of

crystalscrystalsBisphosphonateBisphosphonate

High dose etidronateHigh dose etidronate