Calcium Pyrophosphate Deposition Disease 

  • Author: Constantine K Saadeh, MD; Chief Editor: Herbert S Diamond, MD   more...
 
Updated: Jan 19, 2012
 

Background

Calcium pyrophosphate deposition disease (CPDD) is a metabolic arthropathy caused by the deposition of calcium pyrophosphate dihydrate (CPPD) in and around joints, especially in articular and fibrocartilage. Although CPDD is often asymptomatic, with only radiographic changes (ie, chondrocalcinosis), various clinical manifestations may occur, including acute (pseudogout) and chronic arthritis. Although almost any joint may be involved by CPDD, the knees, wrists, and hips are most commonly affected. This condition is the most common cause of secondary metabolic osteoarthritis.

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Pathophysiology

Although the exact mechanism for the development of CPDD remains unknown, increased adenosine triphosphate breakdown with resultant increased inorganic pyrophosphate in the joints results from aging, genetic factors, or both. Changes in the cartilage matrix may play an important role in promoting CPPD deposition. Rare hereditary forms of CPDD occur, generally inherited in an autosomal dominant mode.

Overactivity of enzymes that break down triphosphates, such as nucleoside triphosphate pyrophosphohydrolase, has been observed in the cartilage of patients with CPDD. Therefore, inorganic pyrophosphate can bind calcium, leading to CPPD deposition in cartilage and synovium.[1, 2] Hyaline cartilage is affected most commonly, but fibrocartilage, such as the meniscal cartilage of the knee, can also be involved.[3]

Hypotheses based on in vitro studies propose that pyrophosphohydrolase activity and inorganic phosphate content, as noted above, are generalized phenomena that occur in fibroblasts.[4] Although these phenomena are generalized, the reason they occur only in joints remains unknown.

Recently, genetic defects have been identified as specific gene mutations in a few kindred families.[5] The mutations occurred in specific genes known as ANKH and COL, which may be involved in crystal-induced inflammation. This is related to synovial tissue and direct cartilage activation, leading to the arthritis caused by CPPD. The ANKH gene has also been shown to be involved in cellular transport of inorganic phosphate.

Gitelman syndrome is associated with both hypokalemic metabolic acidosis and hypomagnesemia. Patients with Gitelman syndrome may have renal tubular acidosis and a history of pseudogout. As such, this diagnosis should be considered in patients with such findings. It has been shown to be associated with a mutation in the gene solute carrier family 12, member 3 (SLC12A3). The cause may be related to the thiazide sensitive sodium chloride cotransporter, which is found in a variant form in most of these patients. The syndrome can mimic several other manifestations of CPDD, including osteoarthritis, carpal tunnel syndrome, and tenosynovitis with calcifications along the tendon sheath itself.[6]

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Epidemiology

Frequency

United States

CPDD is a common condition that occurs with aging in all races. Nearly 50% of people older than 85 years have radiologic evidence of chondrocalcinosis.

Mortality/Morbidity

CPDD can be a cause of significant morbidity, either from the pain of an acute attack of pseudogout or the chronic symptoms associated with chronic arthropathy.

Race

CPDD has no racial predilection.

Sex

CPDD is slightly more common in women than in men, but the exact ratio is unknown. The female-to-male ratio is probably 1.4:1.

Age

CPDD usually occurs in individuals who are in the fifth decade of life or older, with increasing prevalence as age increases. When it occurs early, before the fourth decade of life, it is usually associated with secondary causes, such as an underlying metabolic disease, or familial causes.

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Contributor Information and Disclosures
Author

Constantine K Saadeh, MD  President, Allergy ARTS, LLP; Principal Investigator, Amarillo Center for Clinical Research, Ltd

Constantine K Saadeh, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Rheumatology, American Medical Association, Southern Medical Association, and Texas Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Kristine M Lohr, MD, MS  Professor, Department of Internal Medicine, Center for the Advancement of Women's Health and Division of Rheumatology, Director, Rheumatology Training Program, University of Kentucky College of Medicine

Kristine M Lohr, MD, MS is a member of the following medical societies: American College of Physicians and American College of Rheumatology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Lawrence H Brent, MD  Associate Professor of Medicine, Jefferson Medical College of Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center

Lawrence H Brent, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Physicians, and American College of Rheumatology

Disclosure: Abbott Honoraria Speaking and teaching; Centocor Consulting fee Consulting; Genentech Grant/research funds Other; HGS/GSK Honoraria Speaking and teaching; Omnicare Consulting fee Consulting; Pfizer Honoraria Speaking and teaching; Roche Speaking and teaching; Savient Honoraria Speaking and teaching; UCB Honoraria Speaking and teaching

Alex J Mechaber, MD, FACP  Senior Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine

Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD  Adjunct Professor of Medicine, Division of Rheumatology, University of Pittsburgh School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa

Disclosure: Merck Ownership interest Other; Smith Kline Ownership interest Other; Zimmer Ownership interest Other

Additional Contributors

Thank you to Shannon Shaw and Michael Gaylor for all their hard work on helping prepare this article. The authors and editors of eMedicine also gratefully acknowledge the contributions of previous coauthor, Jan Malacara, PA-C, to the development and writing of this article.

References
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  4. Ryan LM, Wortmann RL, Karas B. Pyrophosphohydrolase activity and inorganic pyrophosphate content of cultured human skin fibroblasts. Elevated levels in some patients with calcium pyrophosphate dihydrate deposition disease. J Clin Invest. May 1986;77(5):1689-93. [Medline].

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  6. Doherty M, Hamilton E, Henderson J. Familial chondrocalcinosis due to calcium pyrophosphate dihydrate crystal deposition in English families. Br J Rheumatol. Feb 1991;30(1):10-5. [Medline].

  7. Ryan LM. Calcium pyrophosphate dihydrate crystal deposition. In: Weyand CM, Wortman R, Klippel JH, eds. Primer on Rheumatic Diseases. 11th ed. Atlanta, Ga: Arthritis Foundation; 1997:226-9.

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  16. Rachow JW, Ryan LM, McCarty DJ. Synovial fluid inorganic pyrophosphate concentration and nucleotide pyrophosphohydrolase activity in basic calcium phosphate deposition arthropathy and Milwaukee shoulder syndrome. Arthritis Rheum. Mar 1988;31(3):408-13. [Medline].

  17. Rothschild BM, Woods RJ. Osteoarthritis, calcium pyrophosphate deposition disease, and osseous infection in Old World primates. Am J Phys Anthropol. Mar 1992;87(3):341-7. [Medline].

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  19. Suan JC, Chhem RK, Gati JS, et al. 4 T MRI of chondrocalcinosis in combination with three-dimensional CT, radiography, and arthroscopy: a report of three cases. Skeletal Radiol. Nov 2005;34(11):714-21. [Medline].

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Calcium pyrophosphate deposition disease. Radiograph of the knee showing chondrocalcinosis involving the meniscal cartilage, also showing evidence of osteoarthritis.
Calcium pyrophosphate deposition disease. Radiograph of the wrist and hand showing chondrocalcinosis of the articular disc of the wrist and atypical osteoarthritis involving the metacarpophalangeal joints in a patient with underlying hemochromatosis.
Calcium pyrophosphate deposition disease. Appearance of calcium pyrophosphate dihydrate crystals obtained from the knee of a patient with pseudogout. The crystals are rhomboid-shaped and weakly positively birefringent as seen by compensated polarized microscopy. The black arrow indicates the direction of the compensator.
Calcium pyrophosphate deposition disease. High-powered view of calcium pyrophosphate dihydrate crystals with compensated polarized microscopy. The black arrow indicates the direction of the compensator. Crystals parallel to compensator are blue, while crystals perpendicular to the compensator are yellow.
Calcium pyrophosphate deposition disease. High-powered view of calcium pyrophosphate dihydrate crystals with compensated polarized microscopy. The crystals parallel to compensator were blue, while crystals perpendicular to the compensator were yellow. However, crystals have been rotated 90%, resulting in a color change in both crystals. The direction of the compensator was unchanged and is indicated by the black arrow.
Wrist chondrocalcinosis.
 
 
 
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