INTRODUCTION — Precipitation of crystals of calcium pyrophosphate dihydrate (CPP) in connective tissues may be asymptomatic or may be associated with several clinical syndromes associated with acute and chronic arthritis. These disorders comprise the spectrum of calcium pyrophosphate crystal deposition (CPPD) disease [1].
The pathogenesis and etiology of CPPD disease will be reviewed here. The clinical manifestations, diagnosis, and treatment of this disorder are discussed separately. (See "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease" and "Treatment of calcium pyrophosphate crystal deposition (CPPD) disease".)
TERMINOLOGY — Calcium pyrophosphate dihydrate (CPP) was formerly abbreviated and commonly referred to as "CPPD" because the dihydrate is necessary for crystallization, but the abbreviation "CPPD" is now reserved for "CPP deposition." Alternative names representing specific clinical or radiographic features of CPPD disease, including pseudogout and chondrocalcinosis, have retained some popularity, but each has limitations:
●Pseudogout/acute CPP crystal arthritis – Pseudogout is a term that has historically been used in two contexts: first, to differentiate the overall concept of CPPD disease from that of monosodium urate crystal deposition disease (gout or urate gout); and second, to describe acute attacks of CPP crystal-induced arthritis clinically resembling those commonly encountered in urate gout. The term "acute CPP crystal arthritis" is now preferred in place of "pseudogout" to describe the latter instance [2].
●Chondrocalcinosis – Chondrocalcinosis refers to radiographic calcification in hyaline cartilage and/or fibrocartilage. It is commonly present in patients with CPPD disease but is neither absolutely specific for CPPD disease nor universal among affected patients.
●CPPD disease – This term refers to the spectrum of clinical manifestations associated with CPP crystal deposition. The term pyrophosphate arthropathy is a historical term that was formerly used to refer to this range of joint disease or radiographic abnormalities associated with CPPD disease.
PATHOGENESIS
CPP crystal formation and deposition — Calcium pyrophosphate dihydrate (CPP) crystal formation is initiated in cartilage located near the surface of chondrocytes, typically in the extracellular matrix near mid-zone chondrocytes [3,4]. The disorder is generally thought to be associated with excessive cartilage pyrophosphate production, leading to local CPP supersaturation and CPP crystal formation or deposition, although aberrations in both mineral and organic phase metabolism are probably variably involved in CPP crystal deposition (CPPD) disease.
While the factors that control CPP crystal formation are not fully delineated, high extracellular pyrophosphate levels in cartilage are necessary for CPP crystal formation. Thus, pyrophosphate metabolism has been the focus of much of the research on the pathophysiology of this disease. High local levels of calcium and alterations in extracellular cartilage matrix also likely contribute to CPPD disease but are less well understood.
Chondrocytes and pyrophosphate — Pyrophosphate is constitutively generated by chondrocytes. It is a potent inhibitor of basic calcium phosphate mineralization. Thus, it prevents normal cartilage matrix from undergoing mineralization with basic calcium phosphate mineral. Factors that increase pyrophosphate levels in cartilage contribute to CPP deposition.
For example, several observations indicate that augmented pyrophosphate production in cartilage extracts from some patients appears to result from overactivity of one or more of a group of nucleoside triphosphate pyrophosphohydrolase (NTPPPH) enzymes [5-7]. These enzymes are associated with the chondrocyte cell membrane and are capable of catalyzing pyrophosphate production by the hydrolysis of extracellular nucleoside triphosphates, especially adenosine triphosphate (ATP) [7]. Ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) is thought to be the most important of the enzymes responsible for NTPPPH activity in cartilage [8-10]. Deficiencies of ENPP1 cause ectopic calcification in mice, supporting a role for ENPP1 in pyrophosphate production and a role of pyrophosphate in inhibiting basic calcium phosphate mineral formation [11].
ANKH protein and pyrophosphate — The ANKH protein is also implicated in CPPD through its actions on pyrophosphate. Deficiencies in ank, the murine analog of the ANKH protein in humans, cause murine progressive ankylosis. In this condition, homozygous nonsense mutations in the ank gene result in reduced extracellular pyrophosphate levels and extensive peripheral and axial skeleton ankylosis with basic calcium phosphate-containing material [12]. The ank gene product is a transmembrane protein, strongly expressed in chondrocytes, which serves either as a pyrophosphate transporter or as a regulator of a channel transporting pyrophosphate or ATP [13]. Thus, conditions that enhance ANKH activity [14,15] could promote CPP crystal formation.
Indeed, a role for ANKH is further supported by the observation that ANKH mutations have been observed in five kindreds with familial CPPD disease [16-19]. In addition, mutations/polymorphisms in or just upstream of the chromosome 5p locus of ANKH have also been identified in some individuals with idiopathic or sporadic CPPD disease [17,20]. Of interest, one such ANKH variant, a -4bp G→A polymorphism in the 5' untranslated promoter region of ANKH, correlates with radiographic chondrocalcinosis that is independent of age or the presence of osteoarthritis, the two most common risk factors for chondrocalcinosis [21].
High ANKH levels may also participate in sporadic CPPD disease. ANKH transcripts and ANKH protein levels are reported to be increased in surgical cartilage specimens from patients with sporadic CPP crystal deposition when compared with control specimens from osteoarthritis patients with no CPP crystal deposition [22].
Other factors — Other factors have been implicated in CPP crystal formation, largely based upon in vitro studies. Cytokines and growth factors, such as transforming growth factor (TGF)-beta, exert dramatic stimulatory effects on chondrocyte pyrophosphate production [23]. Small extracellular vesicles are elaborated by chondrocytes [9] and concentrate ENPP1 enzymes [10]. These vesicles generate CPP crystals in vitro when they are exposed to ATP and are hypothesized to act as foci of CPP crystal formation in the cartilage matrix. Extracellular matrix changes may also promote CPP crystal formation. For example, crosslinking of extracellular matrix proteins by transglutaminase enzymes [24] and increased levels of osteopontin [25] each increase CPP crystal formation in vitro.
Role of CPP crystals in disease — Definitive proof of a causal role of CPP crystals in all of the clinical manifestations with which deposition is associated has not been established, particularly for the degenerative, noninflammatory manifestations of CPPD arthropathy. Nevertheless, compelling evidence for a role of the CPP crystal in acute and subacute joint inflammation is provided by the following observations:
●There are striking similarities in the pathophysiologic mechanisms and clinical appearances of the monosodium urate crystal-induced gout flare and CPP crystal-induced arthritis [26]. Of particular note is the shared capacity of both crystal types to induce NLRP3 NACHT domain-, leucine-rich repeat-, and PYD-containing protein 3 (NALP3)-dependent inflammasome assembly and activation in synovial mononuclear phagocytes and neutrophils. Activation of the NLRP3 inflammasome, in turn, activates latent caspase-1, resulting in interleukin (IL)-1 precursor processing and release of the proinflammatory cytokine IL-1-beta [27]. CPP crystals also induce neutrophil extracellular traps (NETs) that contribute to the inflammation seen in acute CPP crystal arthritis [28].
●The biologic consequences of the interaction of CPP crystals with phagocytic cells (which include mitogenic activation and the release of proinflammatory cytokines) provide a potential basis for the more subacute inflammatory synovitis of CPPD arthropathy [26,29].
●An etiologic or an amplifying role for CPP crystals in the destructive changes in osteoarthritis appears highly likely. The degenerative arthritis accompanying CPPD disease frequently involves such joints as the metacarpophalangeal and wrist joints, which are commonly spared in classical osteoarthritis [30], and chondrocalcinosis appears to be a primary determinant of the rate of radiographically determined joint deterioration in osteoarthritis. Interestingly, in usual osteoarthritis, CPP crystals may not be present in early disease but appear to be secondarily associated with progression of the severity of the osteoarthritis [31]. In a study of cadaveric knees from Japanese older adults (mean age of 78), the deposition of CPP crystals correlated with the degree and depth of cartilage degeneration [32].
CPP crystals also induce factors that promote osteoclastogenesis, providing an additional pathway for crystal-induced joint damage [33]. The observation that patients with osteoarthritis and chondrocalcinosis in the knee have more pain than those with similar degrees of osteoarthritis but without chondrocalcinosis also suggests a possible role of CPPD in osteoarthritis pain [34].
Spontaneous resolution of acute attacks — Acute attacks of CPP crystal arthritis are typically self-limited. Although possible mechanisms for ameliorating inflammation due to CPP crystals have been suggested, a generally accepted explanation is lacking. Phagocytosis and dissolution of crystals may play a role, but observations in patients together with data from animal models indicate that inflammation can abate while crystals are still present in tissue or fluid.
Adhesion of components of extracellular fluid or plasma to crystals may decrease their inflammatory potential. As an example, addition of lipoproteins to CPP crystals reduces their ability to provoke neutrophil phagocytosis and cell lysis in vitro [35]. In an experimental model, the local low-density lipoprotein (LDL) concentration rose within hours after instillation of CPP crystals in association with decreasing inflammation [36]. IL-1-beta receptor antagonists and the formation of extensive NETs may also sequester inflammatory mediators and eventually quell the inflammatory response [37].
ETIOLOGY AND DISEASE ASSOCIATIONS — In most patients, calcium pyrophosphate crystal deposition (CPPD) disease is idiopathic, but joint trauma, familial chondrocalcinosis, and a variety of metabolic and endocrine disorders (table 1), particularly hemochromatosis, are associated with or may cause the illness, especially among younger patients, who are less often affected by CPPD disease than older adults [38] (see "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease", section on 'Post-diagnostic evaluation for associated diseases'):
●Hemochromatosis – Hemochromatosis is clearly associated with the full spectrum of calcium pyrophosphate dihydrate (CPP) crystal-related joint disease, including acute CPP crystal arthritis, chondrocalcinosis, and chronic inflammatory and degenerative arthritis, as was shown in a detailed 1992 literature review of reports of disorders with proposed associations with CPPD disease [38]. A subsequent larger study has also supported the validity of this association [39]. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis" and "Arthritis and bone disease associated with hereditary hemochromatosis".)
●Hyperparathyroidism – The association between hyperparathyroidism and CPPD disease has been described in multiple case reports and is now established in epidemiologic studies. In the United States veteran population, for example, hyperparathyroidism was strongly associated with CPPD disease with an odds ratio of 3.35 (95% CI 2.96-3.79) compared with age- and sex-matched controls [39]. (See "Primary hyperparathyroidism: Clinical manifestations" and "Primary hyperparathyroidism: Clinical manifestations", section on 'Rheumatologic manifestations'.)
●Gout – Gout is also clearly associated with CPPD disease. The coexistence of both monosodium urate and CPP crystals occurs in approximately 5 percent of patients with gout [40]. (See "Clinical manifestations and diagnosis of gout".)
●Hypomagnesemia – Hypomagnesemia has been associated with CPPD disease, initially in case reports, but subsequently, this association has been confirmed in larger studies [39,41]. Hypomagnesemia was a weak risk factor for CPPD disease in the United States veteran population study [39] but was strongly associated with CPPD disease in a study of patients with short bowel syndrome [41]. Gitelman syndrome, an inherited renal tubular disorder resulting in hypokalemia and hypomagnesemia, has also been associated with both chondrocalcinosis and acute CPP crystal arthritis [42,43]. (See "Hypomagnesemia: Causes of hypomagnesemia" and "Hypomagnesemia: Evaluation and treatment" and "Chronic complications of the short bowel syndrome in adults" and "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations".)
●Hypophosphatasia – The association of hypophosphatasia with CPPD disease is largely based upon case reports [38], as the relative rarity of hypophosphatasia has precluded its inclusion in large studies. (See "Epidemiology and etiology of osteomalacia", section on 'Hypophosphatasia'.)
●Joint trauma – Joint trauma (including prior joint surgery) is a demonstrated risk factor for the development of subsequent CPPD disease. As a result, a history of trauma should be sought in younger patients in whom clinical or radiographic evidence of CPPD disease is found. This is particularly true of CPPD noted in the meniscus after meniscal tears [44,45].
●Familial CPPD disease – Familial CPPD disease is typically manifested by an autosomal dominant inheritance and by the occurrence of more severe and widespread arthritis earlier in life than is commonly observed in the typical patient with CPPD disease [1]. (See "Pathogenesis of osteoarthritis", section on 'Aging'.)
Mutations that cause familial CPPD disease cluster in two loci, CCAL1 on 8q and CCAL2 on 5p. As noted, in five pedigrees of familial CPPD disease, the presence of chondrocalcinosis segregated with a mutant form of the human homolog of the ank gene (ANKH) on 5p, which encodes a transmembrane protein that is clearly involved in pyrophosphate regulation [16-19]. (See 'ANKH protein and pyrophosphate' above.)
The TNFRSF11B gene, which codes for osteoprotegerin [46], represents the 8q cluster of mutations that comprise CCAL1 [47]. Initial studies suggest that bone may be the target tissue in patients with this mutation [47,48], but further work to define the mechanisms through which osteoprotegerin contributes to CPPD disease will be necessary. Patients with ANKH mutations often demonstrate chondrocalcinosis prior to joint degeneration, while patients with osteoprotegerin mutations have simultaneous onset of CPPD disease and severe joint degeneration [47]. The frequency of these associations is unknown.
●Other associated disorders and precipitating factors – Other conditions that may be associated with CPPD disease include:
•X-linked hypophosphatemic rickets and familial hypocalciuric hypercalcemia – X-linked hypophosphatemic rickets and familial hypocalciuric hypercalcemia are probably associated with CPPD disease, but the relationship is less clearly demonstrable in these very rare disorders. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia" and "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)
•Osteopenia – An increased frequency of osteopenia has been demonstrated in patients with CPPD disease in the United Kingdom [49], and subsequently, this was also noted in the United States veteran study [39].
•Acromegaly, Wilson disease, and ochronosis – Patients with chondrocalcinosis or CPPD disease in association with acromegaly, Wilson disease, and ochronosis have been reported [38], but it has been challenging to confirm these associations in population-based studies due to the rarity of these conditions. (See "Rheumatologic manifestations of acromegaly" and "Wilson disease: Clinical manifestations, diagnosis, and natural history" and "Disorders of tyrosine metabolism", section on 'Alkaptonuria'.)
•Bisphosphonate administration – Administration of oral bisphosphonates may precipitate attacks of acute CPP crystal arthritis. This was shown in a study from England that found a small increased risk of acute CPP crystal arthritis in patients who had recently received bisphosphonates (incidence rate ratio of 1.33, 95% CI 1.05-1.69) [50].
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Calcium pyrophosphate deposition disease (The Basics)")
●Beyond the Basics topics (see "Patient education: Calcium pyrophosphate crystal deposition (CPPD) disease (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Calcium pyrophosphate dihydrate (CPP) crystal formation is initiated in cartilage located near the surface of chondrocytes. The disorder is generally thought to be associated with excessive cartilage pyrophosphate production, leading to local CPP supersaturation and CPP crystal formation or deposition, although aberrations in both mineral and organic phase metabolism are probably variably involved in calcium pyrophosphate crystal deposition (CPPD) disease. (See 'Pathogenesis' above.)
●There is compelling evidence for a role of the CPP crystal in acute and subacute joint inflammation, although a definitive causal role of CPPD disease in all of the clinical manifestations with which deposition is associated, particularly the noninflammatory changes, has not been established. The typically self-limited nature of acute attacks of CPP crystal arthritis is not well understood. (See 'Role of CPP crystals in disease' above and 'Spontaneous resolution of acute attacks' above.)
●Most cases of CPPD disease are idiopathic, but joint trauma, including prior joint surgery; familial CPPD disease; and a variety of metabolic and endocrine disorders, including hemochromatosis and hyperparathyroidism, are associated with or may cause the illness, particularly among younger patients (table 1). (See 'Etiology and disease associations' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Lawrence Ryan, MD, and Michael A Becker, MD, who contributed to an earlier version of this topic review.
