Pyrophosphate Dihydrate Crystal Deposition Disease Research Articles

Carbonate apatite crystals in primary normophosphatemic tumoral calcinosis

AbstractA 66‐year‐old woman developed firm, painless, slowly growing nodular masses over her elbows, fingers, toes, and left hip over four years. Aspiration of the elbow mass revealed a white chalky material that was shown to be carbonate apatite on infrared spectroscopy and energy dispersive X‐ray spectroscopy. We discuss the classification of tumoral calcinosis and the nature of the calcium deposits. Tumoral calcinosis should be differentiated from tophaceous gout and calcium pyrophosphate dihydrate crystal deposition disease. Polarizing light microscopy and crystal analysis by X‐ray and infrared spectroscopy, electron or X‐ray diffraction will confirm the diagnosis. Secondary causes of tumoral calcinosis should also be excluded.

Calcium pyrophosphate dihydrate crystal deposition disease of the temporomandibular joint

A case of a 74-year-old woman with calcium pyrophosphate dihydrate crystal deposition disease of the temporomandibular joint (TMJ) is presented. This disease rarely involves the TMJ and is not usually considered in the differential diagnosis of TMJ disorders. To our knowledge, only 23 cases have been reported in the literature and only four without any destructive changes of the condyle as in the present case.

Modulation of chondrocyte production of extracellular inorganic pyrophosphate

Extracellular inorganic pyrophosphate (ePPi) both inhibits and promotes different forms of pathologic mineralization. Basic calcium phosphate (BCP) deposition results from depressed levels of ePPi while excess levels of ePPi leads to calcium pyrophosphate dihydrate crystal deposition (CPPD) disease. These crystals are also often identified in patients with osteoarthritis, the most prevalent form of arthritis causing significant morbidity. The two primary hypotheses for generation of ePPi, export of inorganic pyrophosphate through the multipass transmembrane protein ANK and generation of ePPi by ectoenzyme activity, continue to be supported and better understood through animal models and study of families with CPPD deposition disease. As the pathophysiology of crystal formation in both articular cartilage and synovial fluid is better understood, the opportunity for prevention and treatment of pathologic mineralization increases. In particular, a more complex understanding of the ank gene, ectoenzyme PC-1, and the transglutaminase enzyme family may eventually translate into therapeutic application for both BCP deposition and CPPD deposition disease.

Mutations in the amino terminus of ANKH in two US families with calcium pyrophosphate dihydrate crystal deposition disease.

To analyze ANKH in families with calcium pyrophosphate dihydrate crystal deposition disease (CPPD) for disease-causing mutations. Two US families (one of British ancestry and the other of German/Swiss ancestry) with autosomal-dominant CPPD, whose disease phenotypes were found to be linked to chromosome 5p15.1 (locus symbol CCAL2), were screened by direct sequencing for mutations in ANKH, a gene in the CCAL2 candidate interval that has been shown to harbor mutations in other families with CPPD. Observed sequence variants were confirmed by antisense sequencing, and expression of the mutant allele was verified by reverse transcriptase-polymerase chain reaction amplification of messenger RNA followed by direct sequencing. The two US families displayed the same mutation at position 5 of the ANKH gene product (P5T). All affected members were heterozygous for the P-to-T variant, and the mutation was not seen in 204 control alleles. The two families displayed distinct disease haplotypes, suggesting that they were unrelated to each other. These observations represent the fourth and fifth families with heritable CPPD whose disease phenotypes are linked to the CCAL2 locus and who have missense mutations in the amino terminus of ANKH. This same position (P5) was the site of a missense mutation in an Argentine family of northern Italian ancestry; however, the sequence variant in that family generated a P5L mutation. The distinct disease haplotypes among the 3 families with P5 mutations suggest that the mutations arose independently and that the evolutionarily conserved P5 position of ANKH may represent a hot spot for mutation in families with autosomal-dominant CPPD.

Diagnostic usefulness of synovial vascular morphology in chronic arthritis. A systematic survey of 100 cases

Objectives: To assess the diagnostic usefulness of the systematic analysis of synovial vascular morphology in various inflammatory, early, and longstanding arthropathies, and to examine the validity of the vascular patterns in predicting the evolution of a group of patients with undifferentiated arthritis (UA). Methods: One hundred patients who underwent rheumatologic arthroscopy of a symptomatic joint (85 knees, 11 wrists, 3 elbows, 1 metacarpophalangeal joint) were evaluated. The same observer, blinded to patient diagnosis, analyzed the video recordings of the arthroscopies. Vascular morphology was classified into 3 patterns: straight, tortuous, and mixed. Results: Eighty-one patients had inflammatory arthritis: 35 rheumatoid arthritis (RA), 16 psoriatic arthritis (PsA), 13 spondyloarthropathies (SpA), and 17 UA. Forty-nine percent of patients with RA had a straight pattern, 28% a mixed, and 23% a tortuous one. The sensitivity rate of the straight pattern for RA was 77% and the specificity rate was 70%. Seventy-six percent of RA patients with a straight pattern were rheumatoid factor positive (RF+) against 25% of RA patients with a tortuous pattern. The odds ratio for RA associated to straight compared with tortuous pattern was 57.3 (95% confidence interval, 6.6 to 499.5; P < .001). Patients with PsA and SpA shared the same pattern and were analyzed as 1 group. Ninety-three percent of patients with PsA/SpA had a tortuous pattern, 4% a straight pattern, and 3% a mixed pattern. The sensitivity rate of the tortuous pattern for PsA/SpA was 61% and the specificity rate was 95%. During 2 years of follow-up, 6 of 17 patients with UA were definitely diagnosed: 4 RA (2 RF+ and straight pattern; 2 with a tortuous pattern, 1 with RF+ and HLA-B27+); 1 SpA and 1 PsA, both with a tortuous pattern. No differences in vascular patterns were observed according to disease duration. Our results indicate that vascular patterns are not modified by disease modifying antirheumatic drug (DMARD) treatment. The other 19 patients had osteoarthritis (n = 8) and calcium pyrophosphate dihydrate crystal deposition disease (n = 11) and their predominant vascular pattern was tortuous-like. Conclusions: Arthroscopic assessment of synovial vascular changes in chronic arthritis may be of diagnostic and pathogenetic interest, although differences between published studies suggest a need for consensus in evaluating vascular patterns. A straight pattern is strongly associated with RF + RA whereas a tortuous pattern is generally associated with PsA or SpA; these associations are independent of disease duration. The vascular pattern likely does not change qualitatively with DMARD therapy. The application of this technique to the diagnosis or prognosis of patients with UA may be a complementary tool for the treatment of these patients, but larger, prospective studies are necessary to confirm this hypothesis. Semin Arthritis Rheum 32:378-387. © 2003 Elsevier Inc. All rights reserved.

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.

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.

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.

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.

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.

顎関節のピロリン酸カルシウム結晶沈着症（偽痛風）を伴う滑膜軟骨腫症の１例

顎関節のピロリン酸カルシウム結晶沈着症（偽痛風）を伴う滑膜軟骨腫症の１例

Calcium pyrophosphate dihydrate crystal deposition disease after anterior cruciate ligament reconstruction

We report the case of a 34-year-old woman who presented with calcium pyrophosphate dihydrate (CPPD) crystal deposition disease shortly after anterior cruciate ligament (ACL) reconstruction using a polyester artificial ligament (Leeds-Keio; Neoligaments, Leeds, England). The patient had earlier undergone a medial collateral ligament repair of a sprain to her right knee incurred while skiing. Nine years later, she underwent ACL reconstruction. Seventeen months after ACL reconstruction, calcification was observed on radiographs of the medial and lateral menisci. Based on these calcifications and polarized light microscopic findings of the joint fluid, the diagnosis was made of CPPD crystal deposition. CPPD deposition appeared to have resulted from intra-articular damage incurred during ACL reconstruction as well as prolonged anterior instability. Arthroscopy 1998 Sep;14(6):634-6

Crystal-Associated Arthritis

Since the original descriptions of the involvement of crystals in arthritis, understanding of the clinical syndromes of gout and pseudogout and the role of basic calcium crystals in arthritis has increased. Gout is a common problem in middle-aged males but has an increasing prevalence in older patients, particularly women. Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is now a well-recognized problem in older patients. The diagnosis of both 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.