Calcium Pyrophosphate Dihydrate Crystal Deposition Research Articles

Idiopathic Calcium Pyrophosphate Dihydrate (CPPD) Crystal Deposition Disease in a Young Male Patient: A Case Report

Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is a disease of the elderly and extremely rare in young individuals. If young people develop CPPD crystal deposition disease, it may be associated with metabolic diseases such as hemochromatosis, hyperparathyroidism, hypophosphatasia, hypomagnesemia, Wilson's disease, hypothyroidism, gout, acromegaly, and X-linked hypophosphatemic rickets. Therefore, in young-onset polyarticular CPPD crystal deposition disease, investigation for predisposing metabolic conditions is warranted. We report a case of a young male patient with idiopathic CPPD crystal deposition disease, who did not have any evidences of metabolic diseases after thorough evaluations. As far as we know, this is the first report of a young male patient presented with idiopathic CPPD crystal deposition disease.

Calcium pyrophosphate dihydrate crystal deposition disease.

Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is characterized by the accumulation of pyrophosphate dihydrate crystals in articular and periarticular tissues. Various terms have been utilized to describe this arthropathy, which has led to some confusion. CPPD crystal deposition disease is among many conditions that may result in crystal deposition within cartilage. Chondrocalcinosis is a pathologic and radiographic term denoting calcification of cartilage within joints including both hyaline articular cartilage and fibrocartilage. Pseudogout is a clinical term applied to an acute inflammatory process in a joint(s) mimicking a gout attack. Pseudogout is just one of the multiple clinical presentations for CPPD crystal deposition disease. Pyrophosphate arthropathy is a term that has been used to describe the peculiar pattern of joint destruction associated with CPPD crystal deposition disease. This article reviews the protean manifestations of CPPD crystal deposition disease with emphasis on diagnostic imaging.

Up-regulated expression of cartilage intermediate-layer protein and ANK in articular hyaline cartilage from patients with calcium pyrophosphate dihydrate crystal deposition disease.

Excess accumulation of extracellular inorganic pyrophosphate (ePPi) in aged human cartilage is crucial in calcium pyrophosphate dihydrate (CPPD) crystal formation in cartilage matrix. Two sources of ePPi are ePPi-generating ectoenzymes (NTPPPH) and extracellular transport of intracellular PPi by ANK. This study was undertaken to evaluate the role of NTPPPH and ANK in ePPi elaboration, by investigating expression of NTPPPH enzymes (cartilage intermediate-layer protein [CILP] and plasma cell membrane glycoprotein 1 [PC-1]) and ANK in human chondrocytes from osteoarthritic (OA) articular cartilage containing CPPD crystals and without crystals. Chondrocytes were harvested from knee cartilage at the time of arthroplasty (OA with CPPD crystals [CPPD], n = 8; OA without crystals [OA], n = 10). Normal adult human chondrocytes (n = 1) were used as a control. Chondrocytes were cultured with transforming growth factor beta1 (TGFbeta1), which stimulates ePPi elaboration, and/or insulin-like growth factor 1 (IGF-1), which inhibits ePPi elaboration. NTPPPH and ePPi were measured in the media at 48 hours. Media CILP, PC-1, and ANK were determined by dot-immunoblot analysis. Chondrocyte messenger RNA (mRNA) was extracted for reverse transcriptase-polymerase chain reaction to study expression of mRNA for CILP, PC-1, and ANK. NTPPPH and ANK mRNA and protein were also studied in fresh frozen cartilage. Basal ePPi elaboration and NTPPPH activity in conditioned media from CPPD chondrocytes were elevated compared with normal chondrocytes, and tended to be higher compared with OA chondrocytes. Basal expression of mRNA for CILP (chondrocytes) and ANK (cartilage) was higher in both CPPD chondrocytes and CPPD cartilage extract than in OA or normal samples. PC-1 mRNA was less abundant in CPPD chondrocytes and cartilage extract than in OA chondrocytes and extract, although the difference was not significant. CILP, PC-1, and ANK protein levels were similar in CPPD, OA, and normal chondrocytes or cartilage extracts. Both CILP and ANK mRNA expression and ePPi elaboration were stimulated by TGFbeta1 and inhibited by IGF-1 in chondrocytes from all sources. CILP and ANK mRNA expression correlates with chondrocyte ePPi accumulation around CPPD and OA chondrocytes, and all respond similarly to growth factor stimulation. These findings suggest that up-regulated CILP and ANK expression contributes to higher ePPi accumulation from CPPD crystal-forming cartilage.

Autosomal Dominant Familial Calcium Pyrophosphate Dihydrate Deposition Disease Is Caused by Mutation in the Transmembrane Protein ANKH

Familial autosomal dominant calcium pyrophosphate dihydrate (CPPD) chondrocalcinosis has previously been mapped to chromosome 5p15. We have identified a mutation in the ANKH gene that segregates with the disease in a family with this condition. ANKH encodes a putative transmembrane inorganic pyrophosphate (PPi) transport channel. We postulate that loss of function of ANKH causes elevated extracellular PPi levels, predisposing to CPPD crystal deposition.

Animal models of pathologic calcification.

Recent progress in genetics and mouse genomics enables researchers to unveil the molecular basis for mouse phenotypes that express pathologic calcification in soft tissue and/or articular tissues. A newly identified multipass transmembrane protein, ANK, appears to function as an inorganic pyrophosphate (PPi) transporter or regulator of PPi transport. Abnormal extracellular PPi (ePPi) metabolism has been implicated in abnormal calcification, decreased concentrations predisposing to basic calcium phosphate (BCP) deposition, and increased concentrations promoting calcium pyrophosphate dihydrate (CPPD) crystal deposition in articular tissues. The chromosomal location of human ANK overlaps the locus identified in several kindreds affected with familial chondrocalcinosis. Deficient generation of ePPi by the ectoenzyme nucleoside triphosphate pyrophosphohydrolase also results in excessive ossification and ectopic deposition of BCP crystals in tiptoe-walking mice and PC-1 null mice. Recent studies reinforce the important regulatory role of ePPi in pathologic and physiologic calcification.

Tumoural calcium pyrophosphate dihydrate crystal deposition disease presenting clinically as a malignant soft tissue mass diagnosed on fine needle aspiration biopsy

Tumoural calcium pyrophosphate dihydrate crystal deposition is a rare manifestation of calcium pyrophosphate deposition disease (CPPD). We present the case of a 75-year-old male with a previously resected rectal adenocarcinoma who developed a 5-cm right-sided mass at the base of his neck. Clinically and radiologically the lesion was suspicious for malignancy, possibly of metastatic origin. A bedside fine needle aspirate was performed and the smears were mildly cellular showing histiocytes with numerous intracellular and extracellular crystals. These colourless crystals were mostly short and rhomboid shaped and demonstrated weakly positive birefringence. A diagnosis of tumoural CPPD was made. This case is only the second in the English literature diagnosed on fine needle aspiration biopsy. Tumoural CPPD is well known to be a clinical, radiological and occasionally pathological mimic of malignancy. Several cases have been reported where unnecessary radical surgery was performed for this condition. Fine needle aspiration biopsy, as in this case, can provide a rapid and accurate diagnosis of CPPD, avoiding the need for invasive procedures. Polarisation microscopy is a vital adjunct to confirm this diagnosis.

Contribution of digit joint aspiration to the diagnosis of rheumatic diseases

Objectives. To assess the diagnostic usefulness of digit joint aspiration in patients with involvement of one or more digit joints. Patients and methods. All patients who underwent digit joint aspiration during a rheumatology outpatient visit between 1994 and 1998 were included. Fine needles (25 or 28 G) were used, and the aspirate was immediately examined under the microscope to determine the leukocyte count and to look for crystals under polarized light. Results. Digit aspiration yielded a diagnosis of crystal deposition arthropathy in 20 (29%) of the 71 patients (gout, N = 14; calcium pyrophosphate dihydrate crystal deposition disease, N = 6). In 28 patients, the amount of fluid was too small to allow analysis. The leukocyte count indicated inflammatory disease in eight of the remaining 23 patients and mechanical disease in 15. Conclusion. Fine-needle aspiration of symptomatic digit joints provided the diagnosis in two-thirds of patients.

Calcium pyrophosphate dihydrate crystal deposition disease in the temporomandibular joint: Diagnostic difficulties and clonal chromosome aberrations in a case followed up for 5 years

Calcium pyrophosphate dihydrate (CPPD) deposition is a rare disease in the temporomandibular joint (TMJ)1,2 that may, by its unusual location and histology, be mistaken both clinicoradiologically and pathologically for a benign or malignant cartilaginous lesion.3,4 For a definite diagnosis of CPPD arthropathy, a demonstration of rhomboidal crystals on polarized light microscopy is required.

Variations in site and levels of expression of chondrocyte nucleotide pyrophosphohydrolase with aging.

The aim of this study was to identify changes in cartilage intermediate layer protein/nucleotide pyrophosphohydrolase (CILP/NTPPH) expression in articular cartilage during aging. Adult (3-4 years old) and young (7-10 days old) porcine articular hyaline cartilage and fibrocartilage were studied by Northern blot analysis, in situ hybridization, and immunohistochemistry using a complementary DNA (cDNA) probe encoding porcine CILP/NTPPH and antibody to a synthetic peptide corresponding to a CILP/NTPPH sequence. Northern blot analysis of chondrocytes showed lower expression of CILP/NTPPH messenger RNA (mRNA) in young cartilage than in adult cartilage. In adult cartilage, extracellular matrix from the surface to the middeep zone was immunoreactive for CILP/NTPPH, especially in the pericellular matrix surrounding the middeep zone chondrocytes. In young cartilage, chondrocytes were moderately immunoreactive for CILP/NTPPH throughout all zones except the calcified zone. The matrix of young cartilage was negative except in the superficial zone. In young cartilage, CILP/NTPPH mRNA expression was undetectable. In adult cartilage, chondrocytes showed strong mRNA expression for CILP/NTPPH throughout middeep zones. Protein and mRNA signals were not detectable below the tidemark. CILP/NTPPH secretion into matrix around chondrocytes increases with aging. In this extracellular site it may generate inorganic pyrophosphate and contribute to age-related calcium pyrophosphate dihydrate crystal deposition disease.

Calcium crystal-induced inflammation.

Recent studies have added to our knowledge regarding the mechanisms of calcium crystal deposition. Calcium pyrophosphate dihydrate (CPPD) crystal deposition is associated with elevated levels of PPi in joints. Cyclic compression of cartilage transiently elevated ATP levels in culture media. Extracellular ATP may be hydrolyzed by nucleoside triphosphate pyrophosphohydrolase (NTPPPH), yielding an elevated PPi concentration. CPPD crystal deposition increases with age. Nitric oxide may alter cartilage matrix by interfering with chondrocyte mitochondrial function and ATP production. Transglutaminase in adult, but not young, porcine articular chondrocytes was able to activate latent transforming growth factor beta, a potent stimulus to PPi production. Basic calcium phosphate crystals are more likely to form in a milieu of reduced PPi concentration. The ank gene mutation results in higher intracellular PPi concentration and lower extracellular concentration. The ANK protein is thought to be a transmembrane protein necessary for transport of PPi out of cells. A mutation that results in reduced synthesis of NTPPPH PC-1 caused infantile wrist and ankle periarticular calcification and vascular calcification.

Tumoral Calcium Pyrophosphate Dihydrate Crystal Deposition DiseaseA Clinicopathologic Analysis of Five Cases

We describe five cases of tumoral calcium pyrophosphate dihydrate crystal deposition disease (CPPDCD) and discuss the clinical, radiological and pathological features. Patients included 4 males and 1 female, ranging in age from 49 to 70 years (median, 63 yrs). The wrist was involved in two patients. The thumb, palmar aspect of the proximal phalanx of the middle finger and dorsum of the carpal bone of the hand were involved in one patient each. In one patient, a preoperative diagnosis of chondrosarcoma had been made. Macroscopically, the lesion was a circumscribed whitish-gray mass with a more or less chalky appearance, measuring between 1.0 to 6.2 cm (median, 2.5 cm).Histologically, all five lesions contained areas of calcification with crystal deposits and chondroid metaplasia. The majority of crystals were rhomboid in shape, characteristic of CPPD, but some needle-shaped crystals were also identified, which resembled urate crystals. A review of the 54 reported cases of tumoral CPPDCDincluding our series indicated that they could be divided into two categories based on anatomic location: central (head and neck) type (n = 33) and distal (extremity) type (n = 21). Patients of these two groups were not different with respect to age and gender, but those with the central type often presented with a painful mass (15 patients, 46%), or neurological disturbances (11 patients, 33%). Patients with the distal type presented with a painless mass or swelling (12 patients, 57%), but none had neurological signs, although 8 (38.1%) presented with acute attack similar to tophaceous gout. Tumoral CPPDCD should be differentiated from tophaceous gout, tumoral calcinosis, and malignant or benign tumors.

Calcium pyrophosphate dihydrate crystal deposition disease: Imaging perspectives

Calcium pyrophosphate dihydrate (CPPD) crystal is widespread in elderly persons and has various clinical presentation that can be confounding to clinicians. It is characterized by acute, subacute, or chronic joint inflammation and deposition of CPPD crystals in hyaline cartilage, fibrocartilage, and other soft tissue structures. We have learned a great deal about imaging findings of CPPD crystal deposition disease. New facts about the disorder and clues to radiologic diagnosis continue to be revealed. This article will provide a review of imaging characteristics of this disease with emphasis on some recent findings. The nomenclature, epidemiology, classification, and pathophysiology will be explained. A discussion of the clinical manifestations and treatment will be followed by a review of the characteristic imaging features.

CRYSTAL-ASSOCIATED ARTHRITIS IN THE ELDERLY

The understanding of the clinical syndromes of gout and pseudogout, and the role of basic calcium crystals in arthritis has increased since the original descriptions of the involvement of crystals in arthritis. Gout is usually considered an affliction confined to middle aged males but has an increasing prevalence in older populations, with unique and often atypical features. Calcium pyrophosphate dihydrate crystal deposition disease is common in elderly patients. The diagnosis of these common forms of arthritis and the need to individualize therapy in patients with other medical problems remain important clinical challenges to the practicing physician.

Calcium pyrophosphate dihydrate crystal deposition in and around the atlantoaxial joint: association with type 2 odontoid fractures in nine patients.

To investigate the histopathologic anatomy of calcium pyrophosphate dihydrate (CPPD) crystal deposition in and around the atlantoaxial joint and the association between CPPD crystal deposition and subchondral cysts, erosions, and fracture involving the odontoid process of the axis. One adult cadaver demonstrating calcification in the retro-odontoid area at computed tomography (CT) was selected for further radiography, CT, and magnetic resonance (MR) imaging at the C1-2 level. Anatomic sectioning and histologic evaluations were performed in the specimen. For clinical study, radiographs (n = 5), CT scans (n = 8), and MR images (n = 6) in nine patients (mean age, 74.4 years) with odontoid process fractures and CPPD crystal deposits in and around the atlantoaxial joint were reviewed. In the cadaveric specimen, radiography and CT demonstrated calcifications in the transverse ligament; histologic evaluation confirmed that these calcifications were CPPD crystal deposits. In all nine patients, radiography (n = 5) and CT (n = 8) also showed calcification in areas adjacent to the odontoid process, which included the transverse ligament. T1- and T2-weighted MR imaging showed a retro-odontoid mass of low signal intensity that compressed the cervical cord in six patients. CT, MR imaging, or both demonstrated subchondral cysts, osseous erosions, or a type 2 odontoid fracture in all patients. CPPD crystal deposition disease involving the C1-C2 articulation can be a clinically important entity that may place affected patients at increased risk of pathologic fracture of the odontoid process.

ATP release by mechanically loaded porcine chondrons in pellet culture.

To determine whether ATP is released from chondrocytes during mechanical stimulation and whether degradation of ATP generates inorganic pyrophosphate in chondron pellet cultures. Chondron pellets were formed from 1.6 x 10(6) cells that had been enzymatically isolated from porcine articular cartilage. ATP was measured in media from cultures at rest and during fluid movement and cyclic compression. ATP hydrolysis was examined by high-performance liquid chromatography following the addition of gamma32P-ATP to resting cultures. Pellet cultures at rest maintained a steady-state concentration of 2-4 nM ATP in 2 ml of medium. The ATP concentration increased 5-12-fold with cyclic compression (7.5 and 15 kPa at 0.5 Hz), then decreased to preloading levels within 60 minutes despite continued loading. A subsequent increase in pressure stimulated a further increase in ATP release, suggesting that chondrocytes desensitize to load. Cell viability was similar for pellets at rest and up to 24 hours after compression. ATP released in response to mechanical stimulation was inhibited 50% by 0.5 mM octanol, suggesting a regulated mechanism for ATP release. Exogenous ATP was rapidly hydrolyzed to pyrophosphate in resting cultures. The occurrence of basal levels of extracellular ATP in the presence of pyrophosphohydrolase activity indicates that ATP was continuously released by chondrocytes at rest. Considering that chondrocytes express purinoceptors that respond to ATP, we suggest a role for ATP in extracellular signaling by chondrocytes in response to mechanical load. ATP released by chondrocytes in response to mechanical load is a likely source of pyrophosphate in calcium pyrophosphate dihydrate crystal deposition diseases.

What is new about crystals other than monosodium urate?

Recently, attention has focused on the effects of weather conditions and seasonal changes on the incidence of acute microcrystalline events. Acute gout attacks are more frequent during the spring, but seasonal variations in the incidence of acute pseudogout attacks are less clearly defined. Genetic analysis of two unrelated families with calcium pyrophosphate dihydrate (CPPD) crystal deposition disease showed linkage to the short arm of chromosome 5p. Several recent reports show CPPD crystal disease occurring in association with Gitelman syndrome, the hypocalciuric-hypomagnesemic variant of Bartter syndrome. Two signaling pathways, protein kinase C and adenyl cyclase, modulate generation of extracellular pyrophosphate by porcine cartilage chrondrocytes. These transduction mechanisms may provide potential targets for the treatment of CPPD crystal deposition disease. A controlled clinical trial showed ultrasound therapy to be beneficial in the treatment of symptomatic chronic calcific tendinitis of the shoulder. There is evidence that apatite crystals may contribute to cartilage damage in osteoarthritis and that therapeutic interventions to prevent the formation and biologic effects of the crystals may potentially retard the progression of the osteoarthritic process.

顎関節上関節腔洗浄療法にて症状緩解したピロリン酸カルシウム結晶症の１例

We report an unusual case of calcium pyrophosphate dihydrate (CPPD) crystal deposition involving the temporomandibular joint (TMJ) of a 51-year-old woman. The patient presented with a 20-year history of right TMJ clicking sounds without pain and had a locking duration of 6 months with pain. The medical history was unremarkable, and there was no history of disease involving any other joints. There was moderately limited translation of the right condyle and a slight deviation of the mandible to the right during mouth opening. Radiological examination revealed mild bony changes of right condyle, but showed no calcified mass. MRI disclosed anterior disc displacement without reduction. We performed arthrocentesis of the right TMJ and discovered CPPD crystals in the patient's irrigation solution after centrifugation. The crystals were examined by compensated polarized light microscopy and by light microscopy with alizarin red staining. These observations led to a diagnosis of CPPD arthritis of the TMJ. After a 5 years of follow-up, no signs or symptoms of recurrence have been observed.

Calcium pyrophosphate dihydrate crystal deposition disease of the knee simulating spontaneous osteonecrosis.

A retrospective review of the frontal and lateral knee radiographs of 200 patients with calcium pyrophosphate dihydrate (CPPD) crystal deposition disease was performed. Of these 200 patients, nine patients (four male, five female, mean age 74 years, age range 63-87 years) had radiographic findings simulating osteonecrosis of the knee. One patient also had magnetic resonance imaging of the involved knee. A total of 10 knee radiographs in nine patients showed articular and periarticular calcification diagnostic of CPPD crystal deposition of the knee. In addition, all 10 radiographs showed flattening of one femoral condyle. Four of the 10 cases demonstrated an area of radiolucency in the subchondral bone surrounded by a halo of sclerosis. Eight of the 10 cases had narrowing of the involved joint compartment and osteophytosis. These findings mimic the radiographic signs of spontaneous osteonecrosis of the knee. In conclusion, flattening of the femoral condyles in CPPD crystal deposition disease simulates that of spontaneous osteonecrosis and probably relates to articular cartilage and meniscal damage that subsequently leads to stress fracture of subchondral bone with bone collapse.

Deposition of calcium pyrophosphate in tissue after revision arthroplasty of the hip

We reviewed histologically the incidence and pathogenesis of the deposition of calcium pyrophosphate dihydrate (CPPD) crystals in the pseudocapsule, femoral and acetabular membranes and periprosthetic tissue at revision of 789 cases of failed total hip replacement. In 13, periprosthetic tissues were found to have deposits of CPPD crystals in areas of cartilaginous metaplasia; four also showed evidence of localised deposition of amyloid. None of the patients had a history of chondrocalcinosis in the hip or other joints. Cartilaginous metaplasia and other changes in periprosthetic tissues may predispose to the deposition of CPPD and associated localised amyloid.

Deposition of calcium pyrophosphate in tissue after revision arthroplasty of the hip.

We reviewed histologically the incidence and pathogenesis of the deposition of calcium pyrophosphate dihydrate (CPPD) crystals in the pseudocapsule, femoral and acetabular membranes and periprosthetic tissue at revision of 789 cases of failed total hip replacement. In 13, periprosthetic tissues were found to have deposits of CPPD crystals in areas of cartilaginous metaplasia; four also showed evidence of localised deposition of amyloid. None of the patients had a history of chondrocalcinosis in the hip or other joints. Cartilaginous metaplasia and other changes in periprosthetic tissues may predispose to the deposition of CPPD and associated localised amyloid.