Calcium pyrophosphate dihydrate crystal deposition disease

Last updated
Calcium pyrophosphate dihydrate disease
Other namesPseudogout
Birefringence microscopy of pseudogout, annotated.jpg
Polarized light microscopy of CPPD, showing rhombus-shaped calcium pyrophosphate crystals with positive birefringence.
Artistic depiction of pseudogout crystals (calcium pyrophosphate dihydrate crystals) Pseudogout crystals (calcium pyrophosphate dihydrate crystal).png
Artistic depiction of pseudogout crystals (calcium pyrophosphate dihydrate crystals)

Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease, also known as pseudogout and pyrophosphate arthropathy, is a rheumatologic disease which is thought to be secondary to abnormal accumulation of calcium pyrophosphate dihydrate crystals within joint soft tissues. [1] The knee joint is most commonly affected. [2] The disease is metabolic in origin and its treatment remains symptomatic. [3]

Contents

CPPD has also been classified as an Autoimmune Paraneoplastic Manifestation of Myelodysplastic Syndrome. Patients are exhausted of the classification name of "pseudogout" because it alters the course of the doctor/patient conversation and treatment. [ citation needed ]

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 ]


The symptoms can be monoarticular (involving a single joint) or polyarticular (involving several joints). [1] Symptoms usually last for days to weeks, and often recur. Although any joint may be affected, the knees, wrists, and hips are most common. [4]

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. [5] [4] The white blood cell count is often raised. [4]

Cause

Calcium pyrophosphate Calcium pyrophosphate.png
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. [4]

Familial forms are rare. [6] One genetic study found an association between CPPD and a region of chromosome 8q. [7]

The gene ANKH is involved in crystal-related inflammatory reactions and inorganic phosphate transport. [5] [4]

Chrondocalcinosis may be extremely common in the population. CPPD flares may also be triggerd by joint trauma from previous surgeries. Surgery, a necessity for many problems, may cause long-term trauma on the body, even with complete recoveries.

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 ]

X-ray of a knee with chondrocalcinosis. Chondrocalcinosis - annotated.jpg
X-ray of a knee with chondrocalcinosis.

Medical imaging, consisting of x-ray, CT, MRI, or ultrasound may detect chondrocalcinosis within the affected joint, indicating a substantial amount of calcium crystal deposition within the cartilage or ligaments. [2] Ultrasound is a reliable method to diagnose CPPD. [8] Using ultrasound, chondrocalcinosis may be depicted as echogenic foci with no acoustic shadow within the hyaline cartilage [9] or fibrocartilage. [8] By x-ray, CPPD can appear similar to other diseases such as ankylosing spondylitis and gout. [2] [4]

Micrograph showing crystal deposition in an intervertebral disc. H&E stain. Pseudogout - high mag.jpg
Micrograph showing crystal deposition in an intervertebral disc. H&E stain.
CPPD crystals are more clearly visualized on light microscopy without a condenser. Calcium pyrophosphate dihydrate crystals without and with condenser, annotated.jpg
CPPD crystals are more clearly visualized on light microscopy without a 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"). [10] [11] 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. [12] However, even this method has poor sensitivity, specificity, and inter-operator agreement. [12]

These two modalities currently define CPPD disease, but lack diagnostic accuracy. [13] Thus, the diagnosis of CPPD disease is potentially 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. [4] For acute pseudogout, treatments include intra-articular corticosteroid injection, systemic corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), or, on occasion, high-dose colchicine. [4] In general, NSAIDs are administered in low doses to help prevent CPPD. However, if an acute attack is already occurring, higher doses are administered. [4] If nothing else works, hydroxychloroquine or methotrexate may provide relief. [14] Research into surgical removal of calcifications is underway, however, this still remains an experimental procedure. [4]

Based on patient interviews, the only way CPPD pain is managed is with opioids and corticosteroids. Other treatments do not work on the relentless pain and opioid treatment, in most cases, are ignored by clinicians.

NSAIDs, Colchicine, and methotrexate may provide initial relief. However, the digestive system side effects to the liver, kidney, and stomach poisoning, out weigh the risks of opioids.

The patient may experience opioid dependence in lieu of addiction. This side effect is managed by close tapering by the primary care physician. Long-term use of opioids, when taken correctly, would not cause digestive failure.

Managed pain control with opioids is a safe, effective treatment. It prevents ER visits and improves quality of life.

Doctors rarely admit CPPD patients into hospitals or treat in an ER for pain due to current legislative biases on pain management.

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". [3] New, innovative methods using catalytic peptides are in development. [15]

Epidemiology

The condition is more common in older adults. [5]

CPPD is estimated to affect 4% to 7% of the adult populations of Europe and the United States. [16] Previous studies have overestimated the prevalence by simply estimating the prevalence of chondrocalcinosis, which is found in many other conditions as well. [16]

It may cause considerable pain, but it is never fatal. [4] Women are at a slightly higher risk than men, with an estimated ratio of occurrence of 1.4:1. [4]

CPPD itself may not be fatal, however untreated pain may potentially result in death.

History

CPPD crystal deposition disease was originally described over 50 years ago. [13]

The disease may be common in people over 60, yet the research is scant. Instead, it has been categorized as gout. Gout, although a terribly painful disease that attacks the toes has a cure. CPPD, formerly referred to a pseudogout, is not gout. The pain radiates throughout the entire skeleton with no treatment or cure. [ citation needed ]


Clinicians possibly dismiss the pain and disability severity because of lack of reference, qualify it as "just gout", fear of the unknown or DEA retribution. Many have disregarded the pain as a mental condition and recommend psychiatric treatment, which has been proven as false and an injustice to the patient. [ citation needed ]

Interviewed patients had no other comormodies, in good physical condition, and led active lifestyles. Many stated their CPPD has been the worst pain ever experienced and their lives had changed for the worse. [ citation needed ]

Terminology

Calcium pyrophosphate dihydrate crystals are associated with a range of clinical syndromes, which have been given various names, based upon which clinical symptoms or radiographic findings are most prominent. [13] A task force of the European League Against Rheumatism (EULAR) made recommendations on preferred terminology. [6] 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 gouty arthritis (a similar condition in which monosodium urate crystals are deposited within the joints). Chondrocalcinosis, [2] [4] 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. [17]

Related Research Articles

<span class="mw-page-title-main">Arthritis</span> Type of joint disorder

Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In some types of arthritis, other organs are also affected. Onset can be gradual or sudden.

<span class="mw-page-title-main">Gout</span> Form of arthritis causing swollen joints

Gout is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot and swollen joint, caused by the deposition of needle-like crystals of uric acid known as monosodium urate crystals. Pain typically comes on rapidly, reaching maximal intensity in less than 12 hours. The joint at the base of the big toe is affected (Podagra) in about half of cases. It may also result in tophi, kidney stones, or kidney damage.

Rheumatology is a branch of medicine devoted to the diagnosis and management of disorders whose common feature is inflammation in the bones, muscles, joints, and internal organs. Rheumatology covers more than 100 different complex diseases, collectively known as rheumatic diseases, which includes many forms of arthritis as well as lupus and Sjögren's syndrome. Doctors who have undergone formal training in rheumatology are called rheumatologists.

<span class="mw-page-title-main">Joint</span> Location at which two or more bones make contact

A joint or articulation is the connection made between bones, ossicles, or other hard structures in the body which link an animal's skeletal system into a functional whole. They are constructed to allow for different degrees and types of movement. Some joints, such as the knee, elbow, and shoulder, are self-lubricating, almost frictionless, and are able to withstand compression and maintain heavy loads while still executing smooth and precise movements. Other joints such as sutures between the bones of the skull permit very little movement in order to protect the brain and the sense organs. The connection between a tooth and the jawbone is also called a joint, and is described as a fibrous joint known as a gomphosis. Joints are classified both structurally and functionally.

<span class="mw-page-title-main">Osteoarthritis</span> Form of arthritis caused by degeneration of joints

Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone. It is believed to be the fourth leading cause of disability in the world, affecting 1 in 7 adults in the United States alone. The most common symptoms are joint pain and stiffness. Usually the symptoms progress slowly over years. Other symptoms may include joint swelling, decreased range of motion, and, when the back is affected, weakness or numbness of the arms and legs. The most commonly involved joints are the two near the ends of the fingers and the joint at the base of the thumbs, the knee and hip joints, and the joints of the neck and lower back. The symptoms can interfere with work and normal daily activities. Unlike some other types of arthritis, only the joints, not internal organs, are affected.

<span class="mw-page-title-main">Septic arthritis</span> Medical condition

Acute septic arthritis, infectious arthritis, suppurative arthritis, pyogenic arthritis, osteomyelitis, or joint infection is the invasion of a joint by an infectious agent resulting in joint inflammation. Generally speaking, symptoms typically include redness, heat and pain in a single joint associated with a decreased ability to move the joint. Onset is usually rapid. Other symptoms may include fever, weakness and headache. Occasionally, more than one joint may be involved, especially in neonates, younger children and immunocompromised individuals. In neonates, infants during the first year of life, and toddlers, the signs and symptoms of septic arthritis can be deceptive and mimic other infectious and non-infectious disorders.

Rheumatism or rheumatic disorders are conditions causing chronic, often intermittent pain affecting the joints or connective tissue. Rheumatism does not designate any specific disorder, but covers at least 200 different conditions, including arthritis and "non-articular rheumatism", also known as "regional pain syndrome" or "soft tissue rheumatism". There is a close overlap between the term soft tissue disorder and rheumatism. Sometimes the term "soft tissue rheumatic disorders" is used to describe these conditions.

<span class="mw-page-title-main">Baker's cyst</span> Medical condition

A Baker's cyst, also known as a popliteal cyst, is a type of fluid collection behind the knee. Often there are no symptoms. If symptoms do occur these may include swelling and pain behind the knee, or knee stiffness. If the cyst breaks open, pain may significantly increase with swelling of the calf. Rarely complications such as deep vein thrombosis, peripheral neuropathy, ischemia, or compartment syndrome may occur.

<span class="mw-page-title-main">Synovial fluid</span> Fluid found in the cavities of synovial joints

Synovial fluid, also called synovia,[help 1] is a viscous, non-Newtonian fluid found in the cavities of synovial joints. With its egg white–like consistency, the principal role of synovial fluid is to reduce friction between the articular cartilage of synovial joints during movement. Synovial fluid is a small component of the transcellular fluid component of extracellular fluid.

<span class="mw-page-title-main">Tophus</span> Medical condition

A tophus is a deposit of monosodium urate crystals, in people with longstanding high levels of uric acid (urate) in the blood, a condition known as hyperuricemia. Tophi are pathognomonic for the disease gout. Most people with tophi have had previous attacks of acute arthritis, eventually leading to the formation of tophi. Chronic tophaceous gout is known as Harrison Syndrome.

Monoarthritis is inflammation (arthritis) of one joint at a time. It is usually caused by trauma, infection, or crystalline arthritis.

<span class="mw-page-title-main">Arthropathy</span> Medical condition

An arthropathy is a disease of a joint.

<span class="mw-page-title-main">Synovitis</span> Medical condition

Synovitis is the medical term for inflammation of the synovial membrane. This membrane lines joints that possess cavities, known as synovial joints. The condition is usually painful, particularly when the joint is moved. The joint usually swells due to synovial fluid collection.

<span class="mw-page-title-main">Calcium pyrophosphate</span> Chemical compound

Calcium pyrophosphate (Ca2P2O7) is a chemical compound, an insoluble calcium salt containing the pyrophosphate anion. There are a number of forms reported: an anhydrous form, a dihydrate, Ca2P2O7·2H2O and a tetrahydrate, Ca2P2O7·4H2O. Deposition of dihydrate crystals in cartilage are responsible for the severe joint pain in cases of calcium pyrophosphate deposition disease (pseudo gout) whose symptoms are similar to those of gout. Ca2P2O7 is commonly used as a mild abrasive agent in toothpastes, because of its insolubility and nonreactivity toward fluoride.

<span class="mw-page-title-main">Knee effusion</span> Medical condition

Knee effusion, informally known as water on the knee, occurs when excess synovial fluid accumulates in or around the knee joint. It has many common causes, including arthritis, injury to the ligaments or meniscus, or fluid collecting in the bursa, a condition known as prepatellar bursitis.

Arthrocentesis, or joint aspiration, is the clinical procedure performed to diagnose and, in some cases, treat musculoskeletal conditions. The procedure entails using a syringe to collect synovial fluid from or inject medication into the joint capsule. Laboratory analysis of synovial fluid can further help characterize the diseased joint and distinguish between gout, arthritis, and synovial infections such as septic arthritis.

Crystal arthropathy is a class of joint disorder that is characterized by accumulation of tiny crystals in one or more joints. Polarizing microscopy and application of other crystallographic techniques have improved identification of different microcrystals including monosodium urate, calcium pyrophosphate dihydrate, calcium hydroxyapatite, and calcium oxalate.

Milwaukee shoulder syndrome (MSS) (apatite-associated destructive arthritis/Basic calcium phosphate (BCP) crystal arthritis/rapid destructive arthritis of the shoulder is a rare rheumatological condition similar to pseudogout, associated with periarticular or intra-articular deposition of hydroxyapatite or basic calcium phosphate (BCP) crystals. While primarily associated with the shoulder joint, it can affect any joint in the body below the head. Along with symptomatology, the disease typically presents with positive radiologic findings, often showing marked erosion of the humeral head, cartilage, capsule, and bursae. Though rare, it is most often seen in females beginning in their 50s or 60s. Patients often have a history of joint trauma or overuse, calcium pyrophosphate dehydrate crystal deposition, neuroarthropathy, dialysis-related arthropathy or denervation.

<span class="mw-page-title-main">Hip pain</span>

Pain in the hip is the experience of pain in the muscles or joints in the hip/ pelvic region, a condition commonly arising from any of a number of factors. Sometimes it is closely associated with lower back pain.

<span class="mw-page-title-main">Chondrocalcinosis</span> Medical condition

Chondrocalcinosis or cartilage calcification is calcification in hyaline cartilage and/or fibrocartilage. It can be seen on radiography.

References

  1. 1 2 Wright GD, Doherty M (October 1997). "Calcium pyrophosphate crystal deposition is not always 'wear and tear' or aging". Annals of the Rheumatic Diseases. 56 (10): 586–588. doi:10.1136/ard.56.10.586. PMC   1752269 . PMID   9389218.
  2. 1 2 3 4 Rothschild BM, Bruno MA (7 June 2022). Coombs BD, Keats TE (eds.). "Calcium Pyrophosphate Deposition Disease (radiology)".
  3. 1 2 Abhishek A, Doherty M (2016). "Update on calcium pyrophosphate deposition". Clinical and Experimental Rheumatology. 34 (4 Suppl 98): 32–38. PMID   27586801.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 Rothschild BM, Bruno MA (9 April 2021). Coombs BD, Keats TE (eds.). "Calcium Pyrophosphate Deposition Disease (rheumatology)". Medscape.
  5. 1 2 3 Tsui FW (April 2012). "Genetics and mechanisms of crystal deposition in calcium pyrophosphate deposition disease". Current Rheumatology Reports. 14 (2): 155–160. doi:10.1007/s11926-011-0230-6. PMID   22198832. S2CID   41336263.
  6. 1 2 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.
  7. Baldwin CT, Farrer LA, Adair R, Dharmavaram R, Jimenez S, Anderson L (March 1995). "Linkage of early-onset osteoarthritis and chondrocalcinosis to human chromosome 8q". American Journal of Human Genetics. 56 (3): 692–697. PMC   1801178 . PMID   7887424.
  8. 1 2 Filippou G, Adinolfi A, Iagnocco A, Filippucci E, Cimmino MA, Bertoldi I, et al. (June 2016). "Ultrasound in the diagnosis of calcium pyrophosphate dihydrate deposition disease. A systematic literature review and a meta-analysis". Osteoarthritis and Cartilage. 24 (6): 973–981. doi: 10.1016/j.joca.2016.01.136 . hdl: 11392/2365664 . PMID   26826301.
  9. Arend CF. Ultrasound of the Shoulder. Master Medical Books, 2013. Free chapter on acromioclavicular chondrocalcinosis is available at ShoulderUS.com
  10. Hosler G. "calcinosis_cutis_2_060122". Derm Atlas. Archived from the original on 5 February 2007. Retrieved 13 March 2012.
  11. "Calcium Pyrophosphate Dihydrate Deposition Disease: Synovial Biopsy, Wrist". Rheumatology Image Bank. American College of Rheumatology. Retrieved 13 March 2012.
  12. 1 2 Dieppe P, Swan A (May 1999). "Identification of crystals in synovial fluid". Annals of the Rheumatic Diseases. 58 (5): 261–263. doi:10.1136/ard.58.5.261. PMC   1752883 . PMID   10225806.
  13. 1 2 3 Rosenthal AK, Ryan LM (May 2011). "Crystal arthritis: calcium pyrophosphate deposition-nothing 'pseudo' about it!". Nature Reviews. Rheumatology. 7 (5): 257–258. doi: 10.1038/nrrheum.2011.50 . PMID   21532639.
  14. Emkey GR, Reginato AM (2009). "All about gout and pseudogout". Journal of Musculoskeletal Medicine. 26 (10).
  15. Piast RW, Wieczorek RM, Marzec N, Garstka M, Misicka A (September 2021). "A Phage Display-Identified Short Peptide Capable of Hydrolyzing Calcium Pyrophosphate Crystals-The Etiological Factor of Chondrocalcinosis". Molecules. 26 (19): 5777. doi: 10.3390/molecules26195777 . PMC   8510196 . PMID   34641321.
  16. 1 2 Rosenthal AK (2021). Post TW (ed.). "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease". UpToDate . Waltham, MA: UpToDate. This topic last updated: Jul 24, 2018.
  17. Longmore M, Wilkinson I, Turmezei T, Cheung CK (2007). Oxford Handbook of Clinical Medicine. Oxford. p. 841. ISBN   978-0-19-856837-7.