scholarly journals THU0422 CALCIUM PYROPHOSPHATE CRYSTAL DEPOSITION WITHIN TOPHUS LOBULE: A FREQUENT ASSOCIATION OBSERVED IN LONG-TIME COURSE TOPHI

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 449.2-449
Author(s):  
H. K. Ea ◽  
O. Olivier ◽  
N. N. Pham ◽  
V. Frochot ◽  
D. Bazin ◽  
...  
Keyword(s):  
Time Course ◽  
Bone Erosion ◽  
Fibrous Tissue ◽  
Calcium Pyrophosphate ◽  
Small Sample ◽  
Disease Stage ◽  
Crystal Formation ◽  
Crystal Deposition ◽  
Long Time ◽  
Msu Crystals

Background:Calcium pyrophosphate (CPP) crystals and monosodium urate (MSU) crystals are frequently found in the same synovial fluids of gouty patients suggesting an interaction in crystal formation and deposition. This association has never been reported in tophus.Objectives:we aimed to describe the prevalence of CPP crystal deposition in tophus and to determine the associated risk factors.Methods:22 tophi consecutively harvested were fixed in 4% paraformaldehyde and embedded in paraffin. 5-µm thick sections were analyzed by compensated polarized microscopy (CPM) after hematoxylin and eosin staining. Characterization of CPP crystals were performed by scan electronic microscopy (SEM) and Fourier transform infrared (FTIR) spectroscopy. Clinical characteristics were compared between patients having tophus with CPP deposition and patients having tophus without CPP crystals.Results:All tophi appeared multi-lobulated depositions of MSU crystals separated by fibrous tissue and surrounded by a foreign giant cell reaction. CPP crystals were identified in few lobules of 5 tophi (22.7%) harvested from 3 great toes, 1 elbow bursa and 1 finger of 5 patients. CPP crystals formed aggregate deposition within the lobule of MSU crystals. Both monoclinic and triclinic CPP crystal phases were identified by CPM, SEM and FTIR. Tophi were harvested from 22 male gouty patients with a mean age of 50.8 (28-66) years and a mean BMI of 24.2 kg/m2 (18.9-29.4). Mean serum urate level (SUL) was 499 ± 107 µmol/L. 59% of patients had chronic renal disease stage 2 or 3, 40.9% dyslipidemia, 22.7% type 2 diabetes mellitus, 13.6% hypertension and 50% obesity. Patients with tophi containing CPP deposition were older (61.2 [56-66] vs 47.8 [28-64] years, p=0.009) and had a longer gout duration (19 [10-31] vs 9 [3-20] years, p= 0.007) and tophus duration (11.4 [8-16] vs 4.5 [1-9] years, p< 0.0001) than patients with tophi alone. Tophi did not display calcification on radiographies performed before surgery. However, the density of tophi containing CPP crystal deposition was higher than the density of tophi without CPP crystals (51 [25-100] vs 21.5% [0-40], p=0.009). The proportion of bone erosion and gout arthropathy was similar between the two groups. Similarly, no difference was observed for SUL (467 ± 43 vs 509 ± 109 µmol/L), estimated glomerular filtration rate (76.6 ± 11.9 vs 74.9 ± 15.7 ml/min/1.73m2) and prevalence of comorbidities. Interestingly, no calcification was detected on knee and wrist radiographies of patients with tophi containing CPP deposition.Conclusion:These results reported for the first time, in a small sample size, that CPP crystal deposition occurred within tophus lobules. They suggested that long-time course tophi might act as a facilitating agent of CPP nucleation. This hypothesis needs specific confirmation studiesDisclosure of Interests: :None declared

Pathophysiology of gout

2016 ◽  
Author(s):  
Nicola Dalbeth
Keyword(s):  
Inflammatory Response ◽  
Interleukin 1 ◽  
Elevated Serum ◽  
Joint Damage ◽  
Physiological Role ◽  
Crystal Formation ◽  
Acute Inflammatory Response ◽  
Crystal Deposition ◽  
Immune System Activation ◽  
Msu Crystals

The clinical features of gout occur in response to monosodium urate (MSU) crystals. Gout should be considered a chronic disease of MSU crystal deposition. A number of pathophysiological checkpoints are required for development of gout. First, elevated urate concentrations are required: urate overproduction and underexcretion contribute to total urate balance. Overproduction occurs due to alterations in the purine synthesis and degradation pathways. Renal underexcretion is an important cause of elevated serum urate concentrations (hyperuricaemia), and occurs through alterations in the urate transporters within the renal tubule (collectively known as the urate transportasome). Gut underexcretion (extrarenal urate underexcretion) also contributes to development of hyperuricaemia. The next checkpoint is MSU crystal formation. In some individuals with evidence of MSU crystal deposition, symptomatic gout develops. The acute inflammatory response to MSU crystals represents a self-limiting sterile acute auto-inflammatory response which is mediated by the innate immune system activation. Interleukin 1 beta is the key cytokine that contributes to the acute inflammatory response to MSU crystals. In some patients, advanced gout may occur with structural joint damage. Joint damage in gout is mediated both by direct effects of MSU crystals on joint tissue and by indirect effects of joint inflammation. In addition to their central role in pathogenesis of gout, MSU crystals have a physiological role, particularly as an adjuvant or ‘danger signal’ in immune surveillance.

scholarly journals Upregulation of ANK Protein Expression in Joint Tissue in Calcium Pyrophosphate Dihydrate Crystal Deposition Disease

2013 ◽  
Vol 41 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Miwa Uzuki ◽  
Takashi Sawai ◽  
Lawrence M. Ryan ◽  
Ann K. Rosenthal ◽  
Ikuko Masuda
Keyword(s):  
Calcium Pyrophosphate ◽  
Calcium Pyrophosphate Dihydrate ◽  
Crystal Formation ◽  
Type X Collagen ◽  
Crystal Deposition ◽  
Chondrocyte Hypertrophy ◽  
Inorganic Pyrophosphate ◽  
Crystal Deposition Disease ◽  
Cppd Crystal ◽  
Pyrophosphate Dihydrate

Objective.Accumulation of excess extracellular inorganic pyrophosphate leads to calcium pyrophosphate dihydrate (CPPD) crystal formation in articular cartilage. CPPD crystal formation occurs near morphologically abnormal chondrocytes resembling hypertrophic chondrocytes. The ANK protein was recently implicated as an important factor in the transport of intracellular inorganic pyrophosphate across the cell membrane. We characterized ANK in joint tissues from patients with and without CPPD deposition and correlated the presence of ANK with markers of chondrocyte hypertrophy.Methods.Articular tissues were obtained from 24 patients with CPPD crystal deposition disease, 11 patients with osteoarthritis (OA) without crystals, and 6 controls. We determined the number of ANK–positive cells in joint tissues using immunohistochemistry and in situ hybridization, and correlated ANK positivity with markers of chondrocyte hypertrophy including Runx2, type X collagen, osteopontin (OPN), and osteocalcin (OCN).Results.ANK was detected in synoviocytes, chondrocytes, osteoblasts, and osteocytes. ANK was seen extracellularly only in the matrix of cartilage and meniscus. The number of ANK-positive cells was significantly higher in CPPD than in OA or normal joint tissues. The amount and intensity of ANK immunoreactivity reached maximum levels in the large chondrocytes around crystal deposits. ANK was similarly distributed to and significantly correlated with Runx2, type X collagen, OPN, and OCN.Conclusion.ANK levels were higher in articular tissues from patients with CPPD deposition. ANK was concentrated around crystal deposits and correlated with markers of chondrocyte hypertrophy. These findings support a role for ANK in CPPD crystal formation in cartilage.

Pathophysiology of calcium pyrophosphate deposition

2016 ◽  
Author(s):  
Abhishek Abhishek ◽  
Michael Doherty
Keyword(s):  
Dermatan Sulfate ◽  
Relative Concentration ◽  
Middle Layer ◽  
Calcium Pyrophosphate ◽  
Cartilage Matrix ◽  
Crystal Formation ◽  
Crystal Deposition ◽  
Inorganic Pyrophosphate ◽  
S 100 ◽  
Basic Calcium Phosphate Crystal

Calcium pyrophosphate (CPP) dihydrate crystals form extracellularly. Their formation requires sufficient extracellular inorganic pyrophosphate (ePPi), calcium, and pro-nucleating factors. As inorganic pyrophosphate (PPi) cannot cross cell membranes passively due to its large size, ePPi results either from hydrolysis of extracellular ATP by the enzyme ectonucleotide pyrophosphatase/phosphodiesterase 1 (also known as plasma cell membrane glycoprotein 1) or from the transcellular transport of PPi by ANKH. ePPi is hydrolyzed to phosphate (Pi) by tissue non-specific alkaline phosphatase. The level of extracellular PPi and Pi is tightly regulated by several interlinked feedback mechanisms and growth factors. The relative concentration of Pi and PPi determines whether CPP or hydroxyapatite crystal is formed, with low Pi/PPi ratio resulting in CPP crystal formation, while a high Pi/PPi ratio promotes basic calcium phosphate crystal formation. CPP crystals are deposited in the cartilage matrix (preferentially in the middle layer) or in areas of chondroid metaplasia. Hypertrophic chondrocytes and specific cartilage matrix changes (e.g. high levels of dermatan sulfate and S-100 protein) are related to CPP crystal deposition and growth. CPP crystals cause inflammation by engaging with the NALP3 inflammasome, and with other components of the innate immune system, and is marked with a prolonged neutrophilic inflitrate. The pathogenesis of resolution of CPP crystal-induced inflammation is not well understood.

scholarly journals Direct Crystal Formation from Micronized Bone and Lactic Acid: The Writing on the Wall for Calcium-Containing Crystal Pathogenesis in Osteoarthritis?

2018 ◽  
Author(s):  
Anna A. Bulysheva ◽  
Nardos Sori ◽  
Michael P. Francis
Keyword(s):  
Lactic Acid ◽  
Synovial Fluid ◽  
Soft Tissues ◽  
Bone Erosion ◽  
Average Particle Size ◽  
Calcium Oxalate Monohydrate ◽  
Calcium Pyrophosphate ◽  
Sem Analysis ◽  
Crystal Formation ◽  
Average Particle

AbstractIntroductionPathological calcium-containing crystals accumulating in the joints, synovial fluid, and soft tissues are noted in most elderly patients, yet arthritic crystal formation remains idiopathic. Interestingly, elevated lactic acid and bone erosion are frequently among the comorbidities and clinical features of patients with highest incidence of crystal arthropathies. This work shows that bone particulates (modeling bone erosion) dissolve in lactic acid and directly generate crystals, possibly presenting a mechanism for crystal accumulation in osteoarthritis.Methods and ResultsMicronized human bone (average particle size of 160μm x 79μm) completely dissolved in lactic acid in 48 hours, and in synovial fluid with 500mM lactic acid in 5 days, generating birefringent rhomboid and rod-shaped crystals. SEM analysis with energy dispersive x-ray spectroscopy of these crystals showed average dimensions of around 2μm x 40μm, which contained oxygen, calcium and phosphorous at 8.64:1.85:1. Raman spectroscopy of the generated crystals further showed 910/cm and 1049/cm peaks, aligning with calcium oxalate monohydrate and calcium pyrophosphate, respectively.ConclusionsThis work shows that lactic acid and micronized mineralized bone together directly generate calcium-containing crystals. These observations may provide insights into the elusive etiology of arthritis with crystal involvement, possibly indicating lactic acid as a clinical target for treatment.

scholarly journals Performance of Ultrasound in the Clinical Evaluation of Gout and Hyperuricemia

2020 ◽  
Author(s):  
Ling Cao ◽  
Tianyi Zhao ◽  
Chunmei Xie ◽  
Shucong Zheng ◽  
Weiguo Wan ◽  
...  
Keyword(s):  
Risk Factors ◽  
Bone Erosion ◽  
Gouty Arthritis ◽  
Objective Evaluation ◽  
Monosodium Urate ◽  
Crystal Deposition ◽  
Lowering Therapy ◽  
History Of ◽  
Msu Crystals ◽  
Double Contour

Abstract Objective Evaluation of monosodium urate (MSU) crystal deposition and related lesion in joints using ultrasound in gout and hyperuricemia patients. Methods Total 202 gout patients and 43 asymptomatic hyperuricemia patients were included, the clinical data and ultrasounic assessment results were collected and statistically analyzed. Results Deposition of MSU crystals were found in 25.58% (11/43) of the patients with asymptomatic hyperuricemia and 76.24% (154/202) of the patients with gout. In the all examined 1082 joints from gout patients, 33.09% (358/1082) of them were detected MSU crystals. In MSU crystal positive joints, 77.37% (277/358) of them had history of attacks. Among the joints of gouty arthritis, 56.88% (277/487) of them were found MSU crystals. Double contour sign (DCS), hyperechoic aggregate (HAG) and Tophi were found in 32.65% (159/487), 7.80% (38/487) and 24.64% (120/487) of the joints, respectively. DCS and Tophi, but not HAG, appeared inceasingly in gout duration extension. In the patients with more than 15 years of gout history, DCS, Tophi and HAG were found in 48.18%, 40.00%, 6.36% of US assessed joints, respectively. In the gout patients, synovial lesion and bone erosion were found in 17.74% (192/1082) and 7.58% (82/1082) of joints, respectively. Synovial lesion was related with HAG, while bone erosion was related to tophi and DCS. Conclusion HAG is the early sign of MSU crystal deposition in joints. Early urate lowering therapy (ULT) may reduce HAG and ameliorate synovitis and synovial hypertrophy. DCS and tophi are the risk factors of bone erosion. Early ULT should be considered in the gout patients with DCS or tophi.

scholarly journals Crystal Deposition in the Knee and Great Toe Joints of Asymptomatic Gout Patients

1984 ◽  
Vol 77 (9) ◽  
pp. 747-750 ◽  
Author(s):  
T D Kennedy ◽  
C S Higgens ◽  
D F Woodrow ◽  
J T Scott
Keyword(s):  
Calcium Pyrophosphate ◽  
Knee Joints ◽  
Calcium Pyrophosphate Dihydrate ◽  
Acute Gout ◽  
Crystal Deposition ◽  
Fluid Analysis ◽  
Pyrophosphate Dihydrate ◽  
Metatarsophalangeal Joints ◽  
Mtp Joints ◽  
Msu Crystals

Crystal deposition in asymptomatic knee and first metatarsophalangeal (MTP) joints has been studied in 31 patients with previously proven gout. All had had clinical gout in their MTP joints but their knee joints had never been the site of acute gout. Knee arthroscopy was performed permitting synovial membrane inspection, photography and biopsy. Crystalline material was seen in 9 knees (28%) and confirmed histologically as monosodium urate (MSU) in 4 (12.5%). Synovial fluid analysis on 26 samples using a polarizing light microscope demonstrated MSU crystals in 4 (12.5%) and calcium pyrophosphate dihydrate (CPPD) in 2 (6%). Fluid aspirated from 27 of the metatarsophalangeal joints revealed MSU crystals in 14 (52%) and no CPPD crystals.

scholarly journals Performance of Ultrasound in the Clinical Evaluation of Gout and Hyperuricemia

2020 ◽  
Author(s):  
Ling Cao ◽  
Tianyi Zhao ◽  
Xiaoxia Zhu ◽  
Chunmei Xie ◽  
Shucong Zheng ◽  
...  
Keyword(s):  
Risk Factors ◽  
Clinical Evaluation ◽  
Bone Erosion ◽  
Gouty Arthritis ◽  
Monosodium Urate ◽  
Crystal Deposition ◽  
Lowering Therapy ◽  
History Of ◽  
Msu Crystals ◽  
Double Contour

Abstract BackgroundEvaluation of monosodium urate (MSU) crystal deposition and related lesion in joints using ultrasound in gout and hyperuricemia patients. MethodsTotal 202 gout patients and 43 asymptomatic hyperuricemia patients were included, the clinical data and ultrasunic assessment results were collected and statistically analyzed. ResultsDeposition of MSU crystals were found in 25.58% (11/43) of the patients with asymptomatic hyperuricemia and 76.24% (154/202) of the patients with gout. In the all examined 1082 joints from gout patients, 33.09% (358/1082) of them were detected MSU crystals. In MSU crystal positive joints, 77.37% (277/358) of them had history of attacks. Among the joints of gouty arthritis, 56.88% (277/487) of them were found MSU crystals. Double contour sign (DCS), hyperechoic aggregate (HAG) and Tophi were found in 32.65% (159/487), 7.80% (38/487) and 24.64% (120/487) of the joints, respectively. DCS and Tophi, but not HAG, appeared increasingly in gout duration extension. In the patients with more than 15 years of gout history, DCS, Tophi and HAG were found in 48.18%, 40.00%, 6.36% of US assessed joints, respectively. In the gout patients, synovial lesion and bone erosion were found in 17.74% (192/1082) and 7.58% (82/1082) of joints, respectively. Synovial lesion was related with HAG, while bone erosion was related to tophi and DCS. Nephrolithiasis was detected in 20.30% (41/202) of gout patients and 4.65% (2/43) of hyperuricemia patients, indicating nephrolithiasis occurred in more gout patients than in hyperuricemia patients.ConclusionHAG is the early sign of MSU crystal deposition in joints. Early urate lowering therapy (ULT) may reduce HAG and ameliorate synovitis and synovial hypertrophy. DCS and tophi are the risk factors of bone erosion. Early ULT should be considered in the gout patients with DCS or tophi. And nephrolithiasis was remarkably relevant to MSU crystal deposition in joints in gout patients.

scholarly journals THU0406 IDENTIFICATION OF INTRACELLULAR VACUOLES IN SYNOVIAL FLUID WITH CALCIUM PYROPHOSPHATE AND MONOSODIUM URATE CRYSTALS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 440.1-441
Author(s):  
M. L. Peral ◽  
I. Calabuig ◽  
A. Martín-Carratalá ◽  
M. Andrés ◽  
E. Pascual
Keyword(s):  
Clinical Practice ◽  
Synovial Fluid ◽  
Phase Contrast ◽  
Calcium Pyrophosphate ◽  
Monosodium Urate ◽  
Fluid Analysis ◽  
Cytoplasmic Vacuoles ◽  
Contrast Microscopy ◽  
Ordinary Light ◽  
Msu Crystals

Background:Synovial fluid analysis using polarized microscopy is the gold standard for the diagnosis of crystal-related arthritis. In our experience, we have noted that, when calcium pyrophosphate (CPP) crystals are observed, they sometimes appear within intracellular vacuoles. However, this phenomenon is not seen in those samples containing monosodium urate (MSU) crystals. This finding has been scantly reported in the literature, but may be useful in clinical practice to ensure accurate crystal identification.Objectives:Our study aims to assess whether the presence of vacuoles contributes to identifying the type of crystal, and also to gauge the frequency of their presentation.Methods:We conducted an observational study in a rheumatology unit between February and June of 2019. Synovial fluids containing CPP or MSU crystals, obtained in daily clinical practice, were consecutively included for analysis. Two observers simultaneously analyzed the presence of vacuoles by ordinary light and phase contrast microscopy in less than 24 hours after their extraction, using a microscope equipped with two viewing stations. The primary study variable was to determine whether CPP and MSU crystals are seen inside intracellular vacuoles, and to calculate the frequency of this finding for each type of crystal, estimating their 95% confidence interval (95% CI) and comparing rates using Fisher’s exact test.Results:Twenty-one samples were obtained. Data is given in the Table. MSU crystals were present in 7 (33.3%) and CPP crystals in 14 (66.6%). Interestingly, none of the MSU samples showed crystal-containing vacuoles (95% CI 0-35.4%). On the contrary, cytoplasmic vacuoles containing crystals were present in all of the CPP samples (95% CI 78.5-100%). The findings were confirmed by phase-contrast microscopy. Differences were statistically significant (p<0.001).Table.SAMPLES ACCORDING TO TYPE OF MICROCRYSTAL(n=21)SAMPLES WITH VACUOLS(UNDER ORDINARY LIGHT)SAMPLES WITH VACUOLS(UNDER PHASE CONTRAST)CPP (14; 66.6%)14 (100%)(95%CI 78.5-100%)14 (100%)(95%CI 78.5-100%)MSU (7; 33.3%)0 (0%)(95%CI 0-35.4%)0 (0%)(95%CI 0-35.4%)Conclusion:The presence of vacuoles may be a useful and easy way to differentiate MSU and CPP crystals when performing synovial fluid microscopy in clinical practice, since it appears to be a distinctive feature in CPP crystal fluids.References:[1]Kohn NN, Hughes RE, McCarty DJ Jr, Faires JS. The significance of calcium phosphate crystals in the synovial fluid of arthritic patients: the «pseudogout syndrome». II. Identification of crystals. Ann InternMed. 1962 May;56:738-45.[2]Pascual E, Sivera F, Andrés M. Synovial Fluid Analysis for Crystals. CurrOpRheumatol 2011;23:161-169.[3]McCarty DJ, Koopman WJ. Arthritis and allied conditions: A textbook of rheumatology, volumen 1. Lea &amp;Febiger. 1993.[4]Pascual E, Sivera F. Synovial fluid crystal Analysis. En Gout and other crystal arthropathies. Terkeltaub R ed. Elsevier; 2012: p.20-34.[5]Hwang HS, Yang CM, Park SJ, Kim HA. Monosodium Urate Crystal-Induced Chondrocyte Death via Autophagic Process. Int J Mol Sci. 2015 Dec 8;16(12):29265-77.Image 1. Microscopy with ordinary light. Cells with cytoplasmic vacuoles are observed, as well as abundant intra and extracellular CPP crystals.Image 2. Microscopy with phase contrast technique. Cells with intracellular vacuoles are observed inside which have microcrystals with parallelepiped morphology, compatible with CPP.Disclosure of Interests: :None declared

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