INTRODUCTION — Precipitation of crystals of calcium pyrophosphate (CPP) in connective tissues may be asymptomatic or may be associated with several forms of 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 (CPP) crystals were formerly abbreviated and commonly referred to as "CPPD," but the abbreviation "CPPD" now typically refers to "CPP crystal deposition." Chondrocalcinosis refers to radiographic calcification in hyaline cartilage and/or fibrocartilage. It is commonly present in patients with CPPD disease; however, it is neither absolutely specific for CPPD disease nor universal among affected patients. Acute CPP crystal arthritis replaces the term "pseudogout" [2]. Additional information on terminology is presented elsewhere. (See "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease", section on 'Terminology'.)
PATHOGENESIS
CPP crystal formation and deposition — Calcium pyrophosphate (CPP) crystal formation is initiated in the pericellular matrix near midzone chondrocytes in both hyaline cartilage and fibrocartilage [3,4]. 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, much of the research on the pathophysiology of this disease has focused on pyrophosphate metabolism. High local levels of calcium and alterations in extracellular cartilage matrix also likely contribute to calcium pyrophosphate crystal deposition (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 and therefore prevents mineralization in normal cartilage matrix. Factors that increase pyrophosphate levels in cartilage contribute to CPPD.
Most pyrophosphate in cartilage is generated from extracellular adenosine triphosphate (ATP) [5]. Several observations indicate that overactivity of one or more of a group of nucleoside triphosphate pyrophosphohydrolase (NTPPPH) enzymes contribute to this process [6-8]. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is thought to be the most important of the enzymes responsible for NTPPPH activity in cartilage [9-11]. 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 [12].
Alkaline phosphatase is another key enzyme regulating pyrophosphate levels that is responsible for degrading pyrophosphate. Reduced levels of alkaline phosphatase activity, such as those seen with hypophosphatasia, contribute to CPPD disease in affected individuals [13].
ANKH protein and pyrophosphate — The ANKH protein is also implicated in CPPD. Deficiencies in ank, the murine analog of the ANKH protein in humans, result in reduced extracellular pyrophosphate levels and extensive peripheral and axial skeleton ankylosis with basic calcium phosphate-containing material [14]. The ank gene (ANKH) product is a transmembrane protein, strongly expressed in chondrocytes, which serves either as an ATP transporter or, more likely, a regulator of a channel transporting extracellular ATP [5,15]. Thus, conditions that enhance ANKH activity could promote CPP crystal formation [16,17].
A role for ANKH is further supported by the observation that ANKH mutations have been observed in five kindreds with familial CPPD disease [18-21]. 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 [19,22]. 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 (OA), the two most common risk factors for chondrocalcinosis [23].
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 CPPD when compared with control specimens from OA patients with no CPPD [24].
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 [25]. Small extracellular vesicles are elaborated by chondrocytes [10] and concentrate ENPP1 enzymes [11]. 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 [26] and increased levels of osteopontin [27] each increase CPP crystal formation in vitro.
Role of CPP crystals in disease — Definitive proof of a causal role of CPP crystals has not been fully established for the degenerative, noninflammatory manifestations of CPPD arthropathy. However, there is compelling evidence for a role of CPP crystals in acute and subacute joint inflammation. This 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 [28]. Of particular note is the shared capacity of both crystal types to induce NACHT domain-, leucine-rich repeat-, and PYD-containing protein 3 (NLRP3)-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 1 (IL-1) precursor processing and release of the proinflammatory cytokine IL-1-beta [29]. CPP crystals also induce neutrophil extracellular traps (NETs) that contribute to the inflammation seen in acute CPP crystal arthritis [30].
●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 [28,31].
●An etiologic or an amplifying role for CPP crystals in the destructive changes in OA 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 OA [32], and chondrocalcinosis appears to be a primary determinant of the rate of radiographically determined joint deterioration in OA. Interestingly, CPP crystals may not be present early in the disease course of usual OA but appear to be secondarily associated with progression of the severity of the OA [33]. In a study of cadaveric knees from older adults (mean age of 78), the deposition of CPP crystals correlated with the degree and depth of cartilage degeneration [34].
●CPP crystals also induce factors that promote osteoclastogenesis, providing an additional pathway for crystal-induced joint damage [35]. The observation that patients with OA and chondrocalcinosis in the knee have more pain than those with similar degrees of OA but without chondrocalcinosis also suggests a possible role of CPPD in OA pain [36].
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 [37]. In an experimental model, the local low-density lipoprotein (LDL) concentration rose within hours after instillation of CPP crystals in association with decreasing inflammation [38]. IL-1-beta receptor antagonists and the formation of extensive NETs may also sequester inflammatory mediators and eventually quell the inflammatory response [39].
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) are associated with or may cause the illness, especially among younger patients, who are less often affected by sporadic CPPD disease than older adults [40] (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 (CPP) crystal-related joint disease, including acute CPP crystal arthritis, chondrocalcinosis, and chronic inflammatory and degenerative arthritis, as was shown in a detailed literature review of reports of disorders with proposed associations with CPPD disease [40]. A subsequent larger study has also supported the validity of this association [41]. (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 [41]. (See "Primary hyperparathyroidism: Clinical manifestations" and "Primary hyperparathyroidism: Clinical manifestations", section on 'Rheumatologic conditions'.)
Flares of acute CPP crystal arthritis following parathyroidectomy for hyperparathyroidism have been observed [42]; these episodes may be related to abrupt reduction in serum calcium and magnesium levels during postoperative hypoparathyroidism (see "Hungry bone syndrome following parathyroidectomy in patients with end-stage kidney disease"). Such reduction may cause partial dissolution of crystals with subsequent release from the cartilage matrix into the joint fluid, allowing phagocytosis and the phlogistic response of inflammatory cells.
●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 [43]. (See "Clinical manifestations and diagnosis of gout".)
●Hypomagnesemia – Hypomagnesemia has been associated with CPPD disease [41,44]. Hypomagnesemia was a weak risk factor for CPPD disease in the United States veteran population study [41] but was strongly associated with CPPD disease in a study of patients with short bowel syndrome [44]. Gitelman syndrome, an inherited renal tubular disorder resulting in hypokalemia and hypomagnesemia, has also been associated with both chondrocalcinosis and acute CPP crystal arthritis [45,46]. (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, as the relative rarity of hypophosphatasia has precluded its inclusion in large studies [40]. (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 [47,48].
●Familial CPPD disease – Familial CPPD disease typically has an autosomal dominant inheritance. Clinical manifestations include 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. The TNFRSF11B gene, which codes for osteoprotegerin [49], represents the 8q cluster of mutations that comprise CCAL1 [50]. Initial studies suggest that bone may be the target tissue in patients with this mutation, but further work is needed to define the mechanisms through which osteoprotegerin contributes to CPPD disease [50,51]. The 5p cluster is thought to be related to 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 [18-21]. (See 'ANKH protein and pyrophosphate' above.)
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 [50]. 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 [52], and subsequently this was also noted in the United States veteran study [41].
•Acromegaly, Wilson disease, and ochronosis – Patients with chondrocalcinosis or CPPD disease in association with acromegaly, Wilson disease, and ochronosis have been reported [40], 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 [IRR] 1.33, 95% CI 1.05-1.69) [53].
•Other drug associations – Some [54,55], but not all [41], studies have suggested a potential association between diuretics and CPPD. In addition, use of proton pump inhibitors and H2 blockers may be more frequent among patients with CPPD disease than in age-matched controls [55,56]. While hypomagnesemia is often invoked as a potential mechanism for all of these drugs, these findings remain inconsistent and warrant further investigation.
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SUMMARY
●Calcium pyrophosphate (CPP) crystal formation and deposition – Calcium pyrophosphate (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.)
●Role of CPP crystals in disease – 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.)
●Etiology and disease associations – 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.
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