View source for Calcium pyrophosphate dihydrate crystal deposition disease

{{Infobox medical condition (new)
| name            = Calcium pyrophosphate dihydrate disease
| image           = Birefringence microscopy of pseudogout, annotated.jpg
| caption         = Polarized light microscopy of CPPD, showing rhombus-shaped calcium pyrophosphate crystals with positive [[birefringence]].
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| synonyms        =  Pseudogout
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[[File:Pseudogout crystals (calcium pyrophosphate dihydrate crystal).png|thumb|264x264px|Artistic depiction of pseudogout crystals (calcium pyrophosphate dihydrate crystals)]]
'''Calcium pyrophosphate dihydrate''' ('''CPPD''') '''crystal deposition disease''',<!--this is the umbrella term, and may be better as article title--> also known as '''pseudogout''' and '''pyrophosphate arthropathy''', is a [[rheumatology|rheumatologic]] disease which is thought to be secondary to abnormal accumulation of [[calcium pyrophosphate]] dihydrate crystals within joint soft tissues.<ref name="Wright1997" /> The [[knee|knee joint]] is most commonly affected.<ref name="emedicine1"/> The disease is metabolic in origin and its treatment remains symptomatic.<ref name=":0">{{cite journal | vauthors = Abhishek A, Doherty M | title = Update on calcium pyrophosphate deposition | journal = Clinical and Experimental Rheumatology | volume = 34 | issue = 4 Suppl 98 | pages = 32–38 | date = 2016 | pmid = 27586801 | url = https://pubmed.ncbi.nlm.nih.gov/27586801 }}</ref>
==Signs and symptoms==
When symptomatic, the disease classically begins with symptoms that are similar to a [[gout]] attack (thus the moniker ''pseudogout''). These include:{{citation needed|date=October 2020}}
* severe pain
* warmth
* swelling of one or more joints
* severe fatigue
* fever
* feeling of malaise or [[influenza|flu]]-like symptoms
* inability to walk or perform everyday tasks or hobbies
* gnawing/chewing sensations in the joints
* burning
The symptoms can be monoarticular (involving a single joint) or polyarticular (involving several joints).<ref name="Wright1997" /> Symptoms usually last for days to weeks, and often recur. Although any joint may be affected, the knees, wrists, and hips are most common.<ref name="emedicine2" />
CPPD crystals appear as shattered glass under the microscope. When released into the synovial fluid, it causes unbearable pain to the patient.
Flares are sudden, severe and without warning.  Diet does not appear to cause flares.  Overexertion of any exercise, standing too long, shopping, stressful or loud environments, can or may lead to severe flares, which can last from one hour to months.   Although,  in some patient interviews, alcohol may be a known trigger.
X-ray, CT, or other imaging usually shows accumulation of calcium within the joint cartilage, known as chondrocalcinosis. There can also be findings of [[osteoarthritis]].<ref name="Tsui2012" /><ref name="emedicine2">{{cite journal | vauthors = Rothschild BM, Bruno MA | date = 9 April 2021 | veditors = Coombs BD, Keats TE | title = Calcium Pyrophosphate Deposition Disease (rheumatology) | journal = Medscape | url = https://emedicine.medscape.com/article/388348-overview# }}</ref>  The [[white blood cell]] count is often raised.<ref name="emedicine2" />
==Cause==
[[Image:Calcium pyrophosphate.png|thumb|[[Calcium pyrophosphate]]]]
The cause of CPPD disease is unknown. Increased breakdown of [[adenosine triphosphate]] (ATP; the molecule used as energy currency in all living things), which results in increased pyrophosphate levels in joints, is thought to be one reason why crystals may develop.<ref name="emedicine2"/>
[[Heredity|Familial]] forms are rare.<ref name="Zhang2011"/> One genetic study found an association between CPPD and a region of chromosome 8q.<ref name="Baldwin1995"/>
The gene [[ANKH]] is involved in crystal-related inflammatory reactions and inorganic phosphate transport.<ref name="Tsui2012" /><ref name="emedicine2"/>
Chrondocalcinosis may be extremely common in the population.  CPPD flares may also be triggered by joint trauma from previous surgeries.
==Diagnosis==
The disease is defined by presence of joint inflammation and the presence of CPPD crystals within the joint. The crystals are usually detected by imaging and/or joint fluid analysis.{{citation needed|date=October 2020}}
[[File:Chondrocalcinosis - annotated.jpg|thumb|[[Projectional radiography|X-ray]] of a knee with [[chondrocalcinosis]].]]
Medical imaging, consisting of [[Radiography|x-ray]], [[Computed Tomography|CT]], [[Magnetic Resonance Imaging|MRI]], or [[Medical ultrasound|ultrasound]] may detect [[chondrocalcinosis]] within the affected joint, indicating a substantial amount of calcium crystal deposition within the cartilage or ligaments.<ref name="emedicine1"/> Ultrasound is a reliable method to diagnose CPPD.<ref name="Filippou 2016">{{cite journal | vauthors = Filippou G, Adinolfi A, Iagnocco A, Filippucci E, Cimmino MA, Bertoldi I, Di Sabatino V, Picerno V, Delle Sedie A, Sconfienza LM, Frediani B, Scirè CA | display-authors = 6 | title = Ultrasound in the diagnosis of calcium pyrophosphate dihydrate deposition disease. A systematic literature review and a meta-analysis | journal = Osteoarthritis and Cartilage | volume = 24 | issue = 6 | pages = 973–981 | date = June 2016 | pmid = 26826301 | doi = 10.1016/j.joca.2016.01.136 | doi-access = free | hdl = 11392/2365664 | hdl-access = free }}</ref> Using ultrasound, chondrocalcinosis may be depicted as echogenic foci with no acoustic shadow within the hyaline cartilage<ref>Arend CF. Ultrasound of the Shoulder. Master Medical Books, 2013. Free chapter on acromioclavicular chondrocalcinosis is available at [http://www.shoulderus.com/ultrasound-of-the-shoulder/acromioclavicular-joint-ultrasound-chondrocalcinosis/ ShoulderUS.com]</ref> or fibrocartilage.<ref name="Filippou 2016"/>  By x-ray, CPPD can appear similar to other diseases such as [[ankylosing spondylitis]] and [[gout]].<ref name="emedicine1"/><ref name="emedicine2"/>
[[File:Pseudogout_-_high_mag.jpg|thumb|[[Micrograph]] showing crystal deposition in an [[intervertebral disc]]. [[H&E stain]].]]
[[File:Calcium pyrophosphate dihydrate crystals without and with condenser, annotated.jpg|thumb|CPPD crystals are more clearly visualized on light microscopy without a [[condenser (optics)|condenser]].]]
[[Arthrocentesis]], or removing synovial fluid from the affected joint, is performed to test the synovial fluid for the calcium pyrophosphate crystals that are present in CPPD. When stained with [[H&E stain]], calcium pyrophosphate crystals appears deeply blue ("[[basophilic]]").<ref name=derm_atlas>{{cite web| vauthors = Hosler G |title=calcinosis_cutis_2_060122|work=Derm Atlas|url=http://dermatlas.med.jhmi.edu/derm/IndexDisplay.cfm?ImageID=-512163574|access-date=13 March 2012|archive-url=https://web.archive.org/web/20070205214851/http://dermatlas.med.jhmi.edu/derm/IndexDisplay.cfm?ImageID=-512163574|archive-date=5 February 2007|url-status=dead}}</ref><ref>{{cite web|title=Calcium Pyrophosphate Dihydrate Deposition Disease: Synovial Biopsy, Wrist|url=http://images.rheumatology.org/viewphoto.php?imageId=2862283&albumId=75676|work=Rheumatology Image Bank|publisher=American College of Rheumatology|access-date=13 March 2012}}</ref> However, CPP crystals are much better known for their [[rhomboid]] shape and weak positive [[birefringence]] on polarized light microscopy, and this method remains the most reliable method of identifying the crystals under the microscope.<ref name=dieppe>{{cite journal | vauthors = Dieppe P, Swan A | title = Identification of crystals in synovial fluid | journal = Annals of the Rheumatic Diseases | volume = 58 | issue = 5 | pages = 261–263 | date = May 1999 | pmid = 10225806 | pmc = 1752883 | doi = 10.1136/ard.58.5.261 }}</ref> However, even this method has poor sensitivity, specificity, and inter-operator agreement.<ref name=dieppe />
These two modalities currently define CPPD disease, but lack diagnostic accuracy.<ref name="Rosenthal2011" /> Thus, the diagnosis of CPPD disease is potentially [[epiphenomena|epiphenomenological]].
==Treatment==
Because any medication that could reduce the inflammation of CPPD bears a risk of causing organ damage, treatment is not advised if the condition is not causing pain.<ref name="emedicine2"/>
For [[Acute (medicine)|acute]] pseudogout, treatments include intra-articular corticosteroid injection, systemic corticosteroids, [[non-steroidal anti-inflammatory drugs]] (NSAIDs), or, on occasion, high-dose [[colchicine]].<ref name="emedicine2"/> In general, NSAIDs are administered in low doses to help prevent CPPD. However, if an acute attack is already occurring, higher doses are administered.<ref name="emedicine2"/> If nothing else works, [[hydroxychloroquine]] or [[methotrexate]] may provide relief.<ref>{{Cite journal |vauthors=Emkey GR, Reginato AM |title=All about gout and pseudogout |journal=Journal of Musculoskeletal Medicine |volume=26 |issue=10 |year=2009 |url= http://www.musculoskeletalnetwork.com/display/article/1145622/1476306}}</ref>
Research into surgical removal of calcifications is underway, however, this still remains an experimental procedure.<ref name="emedicine2"/>
NSAIDs, Colchicine, and methotrexate may provide initial relief. There is currently no treatment for non-invasive removal of these crystals once they are deposited. Attempts to dissolve crystals in situ using enzymes turned up to be a "clinical failure".<ref name=":0" /> New, innovative methods using catalytic peptides are in development.<ref>{{cite journal | vauthors = Piast RW, Wieczorek RM, Marzec N, Garstka M, Misicka A | title = A Phage Display-Identified Short Peptide Capable of Hydrolyzing Calcium Pyrophosphate Crystals-The Etiological Factor of Chondrocalcinosis | journal = Molecules | volume = 26 | issue = 19 | pages = 5777 | date = September 2021 | pmid = 34641321 | pmc = 8510196 | doi = 10.3390/molecules26195777 | doi-access = free }}</ref>
==Epidemiology==
The condition is more common in older adults.<ref name="Tsui2012" />
CPPD is estimated to affect 4% to 7% of the adult populations of Europe and the United States.<ref name=uptodate>{{cite web|url=https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-calcium-pyrophosphate-crystal-deposition-cppd-disease|title=Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease| vauthors = Rosenthal AK |website=[[UpToDate]] | veditors = Post TW | publisher = UpToDate | location = Waltham, MA | date = 2021 }} This topic last updated: Jul 24, 2018.</ref> Previous studies have overestimated the prevalence by simply estimating the prevalence of [[chondrocalcinosis]], which is found in many other conditions as well.<ref name=uptodate/>
It may cause considerable pain, but it is never fatal.<ref name="emedicine2" /> Women are at a slightly higher risk than men, with an estimated ratio of occurrence of 1.4:1.<ref name="emedicine2" />
==History==
{{Citations needed|section|date=October 2023}}
{{POV section|date=October 2023}}
CPPD crystal deposition disease was originally described over 50 years ago.<ref name="Rosenthal2011" />
==Terminology==
[[Calcium pyrophosphate|Calcium pyrophosphate dihydrate]] [[crystal]]s are associated with a range of clinical [[syndrome]]s, which have been given various names, based upon which clinical [[symptom]]s or radiographic findings are most prominent.<ref name="Rosenthal2011"/>  A task force of the European League Against Rheumatism (EULAR) made recommendations on preferred [[terminology]].<ref name="Zhang2011"/>  Accordingly, ''calcium pyrophosphate deposition'' (CPPD) is an umbrella term for the various clinical subsets, whose naming reflects an emphasis on particular features. For example, ''pseudogout'' refers to the acute symptoms of joint inflammation or [[synovitis]]: red, tender, and swollen joints that may resemble [[gout]]y arthritis (a similar condition in which [[monosodium urate crystals]] are deposited within the joints). [[Chondrocalcinosis]],<ref name="emedicine1">{{cite web | vauthors = Rothschild BM, Bruno MA | date = 7 June 2022| veditors = Coombs BD, Keats TE | title = Calcium Pyrophosphate Deposition Disease (radiology) | url = https://emedicine.medscape.com/article/388348-overview# }}</ref><ref name="emedicine2"/> on the other hand, refers to the radiographic evidence of calcification in [[hyaline]] and/or [[fibrocartilage]]. "Osteoarthritis (OA) with CPPD" reflects a situation where [[osteoarthritis]]  features are the most apparent. ''Pyrophosphate arthropathy'' refers to several of these situations.<ref name="Longmore2007"/>
== References ==
{{Reflist|2|refs=
<ref name="Baldwin1995">{{cite journal | vauthors = Baldwin CT, Farrer LA, Adair R, Dharmavaram R, Jimenez S, Anderson L | title = Linkage of early-onset osteoarthritis and chondrocalcinosis to human chromosome 8q | journal = American Journal of Human Genetics | volume = 56 | issue = 3 | pages = 692–697 | date = March 1995 | pmid = 7887424 | pmc = 1801178 }}</ref>
<ref name="Longmore2007">{{Cite book| vauthors = Longmore M, Wilkinson I, Turmezei T, Cheung CK | title = Oxford Handbook of Clinical Medicine | publisher = Oxford | year = 2007 | isbn = 978-0-19-856837-7 | page = 841 }}</ref>
<ref name="Rosenthal2011">{{cite journal | vauthors = Rosenthal AK, Ryan LM | title = Crystal arthritis: calcium pyrophosphate deposition-nothing 'pseudo' about it! | journal = Nature Reviews. Rheumatology | volume = 7 | issue = 5 | pages = 257–258 | date = May 2011 | pmid = 21532639 | doi = 10.1038/nrrheum.2011.50 | doi-access = free }}</ref>
<ref name="Tsui2012">{{cite journal | vauthors = Tsui FW | title = Genetics and mechanisms of crystal deposition in calcium pyrophosphate deposition disease | journal = Current Rheumatology Reports | volume = 14 | issue = 2 | pages = 155–160 | date = April 2012 | pmid = 22198832 | doi = 10.1007/s11926-011-0230-6 | s2cid = 41336263 }}</ref>
<ref name="Wright1997">{{cite journal | vauthors = Wright GD, Doherty M | title = Calcium pyrophosphate crystal deposition is not always 'wear and tear' or aging | journal = Annals of the Rheumatic Diseases | volume = 56 | issue = 10 | pages = 586–588 | date = October 1997 | pmid = 9389218 | pmc = 1752269 | doi = 10.1136/ard.56.10.586 }}</ref>
<ref name="Zhang2011">Zhang W, Doherty M, Bardin T, Barskova V, Guerne PA, Jansen TL, Leeb BF, Perez-Ruiz F, Pimentao J, Punzi L, Richette P, Sivera F, Uhlig T, Watt I, Pascual E. European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis. Ann Rheum Dis. 2011;70(4):563.</ref>
}}
{{Medical resources
|   DiseasesDB     = 10832
|   ICD11          = {{ICD11|FA26.0}}
|   ICD10          = {{ICD10|M11.1}}, {{ICD10|M11.2}}
|   ICD9           = {{ICD9|275.49 [712.3]}}
|   ICDO           =
|   OMIM           = 600668
|   OMIM_mult      = {{OMIM|118600||none}}
|   MedlinePlus    = 000421
|   eMedicineSubj  = med
|   eMedicineTopic = 1938
|   eMedicine_mult = {{eMedicine2|radio|125}} {{eMedicine2|orthoped|382}} {{eMedicine2|emerg|221}}
|   MeshID         = D002805
}}
{{Diseases of the musculoskeletal system and connective tissue}}
[[Category:Arthritis]]
[[Category:Inflammatory polyarthropathies]]
[[Category:Musculoskeletal disorders]]
[[Category:Crystal deposition diseases]]