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. The

knee joint In humans and other primates, the knee joins the thigh with the leg and consists of two joints: one between the femur and tibia (tibiofemoral joint), and one between the femur and patella (patellofemoral joint). It is the largest joint in the ...

is most commonly affected. The disease is metabolic in origin and its treatment remains symptomatic.

Signs and symptoms

When symptomatic, the disease classically begins with symptoms that are similar to a

gout Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of pain in a red, tender, hot, and Joint effusion, swollen joint, caused by the deposition of needle-like crystals of uric acid known as monosodium urate crysta ...

attack (thus the moniker ''pseudogout''). These include: * severe pain * warmth * swelling of one or more joints * severe fatigue * fever * feeling of malaise or 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). Symptoms usually last for days to weeks, and often recur. Although any joint may be affected, the knees, wrists, and hips are most common. 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 Osteoarthritis is a type of degenerative joint disease that results from breakdown of articular cartilage, joint cartilage and underlying bone. A form of arthritis, it is believed to be the fourth leading cause of disability in the world, affect ...

. The

white blood cell White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...

count is often raised.

Cause

The cause of CPPD disease is unknown. Increased breakdown of

adenosine triphosphate Adenosine triphosphate (ATP) is a nucleoside triphosphate that provides energy to drive and support many processes in living cell (biology), cells, such as muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all known ...

(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. Familial forms are rare. One genetic study found an association between CPPD and a region of chromosome 8q. The gene ANKH is involved in crystal-related inflammatory reactions and inorganic phosphate transport. 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. Chondrocalcinosis - annotated

Medical imaging, consisting of

x-ray An X-ray (also known in many languages as Röntgen radiation) is a form of high-energy electromagnetic radiation with a wavelength shorter than those of ultraviolet rays and longer than those of gamma rays. Roughly, X-rays have a wavelength ran ...

, CT, MRI, or

ultrasound Ultrasound is sound with frequency, frequencies greater than 20 Hertz, kilohertz. This frequency is the approximate upper audible hearing range, limit of human hearing in healthy young adults. The physical principles of acoustic waves apply ...

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

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 Hematoxylin and eosin stain ( or haematoxylin and eosin stain or hematoxylin–eosin stain; often abbreviated as H&E stain or HE stain) is one of the principal tissue stains used in histology. It is the most widely used stain in medical diag ...

, calcium pyrophosphate crystals appears deeply blue (" basophilic"). However, CPP crystals are much better known for their

rhomboid Traditionally, in two-dimensional geometry, a rhomboid is a parallelogram in which adjacent sides are of unequal lengths and angles are non-right angled. The terms "rhomboid" and "parallelogram" are often erroneously conflated with each oth ...

shape and weak positive

birefringence Birefringence, also called double refraction, is the optical property of a material having a refractive index that depends on the polarization and propagation direction of light. These optically anisotropic materials are described as birefrin ...

on polarized light microscopy, and this method remains the most reliable method of identifying the crystals under the microscope. However, even this method has poor sensitivity, specificity, and inter-operator agreement. These two modalities currently define CPPD disease, but lack diagnostic accuracy. 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. For acute pseudogout, treatments include intra-articular corticosteroid injection, systemic corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), or, on occasion, high-dose

colchicine Colchicine is a medication used to prevent and treat gout, to treat familial Mediterranean fever and Behçet's disease, and to reduce the risk of myocardial infarction. The American College of Rheumatology recommends colchicine, nonstero ...

. In general, NSAIDs are administered in low doses to help prevent CPPD. However, if an acute attack is already occurring, higher doses are administered. If nothing else works, hydroxychloroquine or methotrexate may provide relief. Research into surgical removal of calcifications is underway, however, this still remains an experimental procedure. 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". New, innovative methods using catalytic peptides are in development.

Epidemiology

The condition is more common in older adults. CPPD is estimated to affect 4% to 7% of the adult populations of Europe and the United States. This topic last updated: Jul 24, 2018. Previous studies have overestimated the prevalence by simply estimating the prevalence of chondrocalcinosis, which is found in many other conditions as well. It may cause considerable pain, but it is never fatal. Women are at a slightly higher risk than men, with an estimated ratio of occurrence of 1.4:1.

History

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

Terminology

Calcium pyrophosphate dihydrate

crystal A crystal or crystalline solid is a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a highly ordered microscopic structure, forming a crystal lattice that extends in all directions. In addition, macros ...

s are associated with a range of clinical

syndrome A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease or disorder. The word derives from the Greek language, Greek σύνδρομον, meaning "concurrence". When a sy ...

s, which have been given various names, based upon which clinical

symptom Signs and symptoms are diagnostic indications of an illness, injury, or condition. Signs are objective and externally observable; symptoms are a person's reported subjective experiences. A sign for example may be a higher or lower temperature ...

s or radiographic findings are most prominent. A task force of the European League Against Rheumatism (EULAR) made recommendations on preferred

terminology Terminology is a group of specialized words and respective meanings in a particular field, and also the study of such terms and their use; the latter meaning is also known as terminology science. A ''term'' is a word, Compound (linguistics), com ...

. 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

y arthritis (a similar condition in which monosodium urate crystals are deposited within the joints). Chondrocalcinosis, on the other hand, refers to the radiographic evidence of calcification in

hyaline A hyaline substance is one with a glassy appearance. The word is derived from , and . Histopathology Hyaline cartilage is named after its glassy appearance on fresh gross pathology. On light microscopy of H&E stained slides, the extracellula ...

and/or

fibrocartilage Fibrocartilage consists of a mixture of white fibrous tissue and cartilaginous tissue in various proportions. It owes its inflexibility and toughness to the former of these constituents, and its elasticity to the latter. It is the only type of ...

. "Osteoarthritis (OA) with CPPD" reflects a situation where

features are the most apparent. ''Pyrophosphate arthropathy'' refers to several of these situations.

References

{{Diseases of the musculoskeletal system and connective tissue Arthritis Inflammatory polyarthropathies Musculoskeletal disorders Crystal deposition diseases