Association between serum zinc and copper concentrations and copper/zinc ratio with the prevalence of knee chondrocalcinosis: a cross-sectional study.

BACKGROUND: Patients with chondrocalcinosis may suffer from a series of symptoms resembling acute gouty arthritis or septic arthritis, but the aetiology and pathogenesis of chondrocalcinosis have not been fully elucidated yet. This study was aimed to assess serum zinc and copper concentrations, as well as the ratio of serum copper to zinc concentrations (Cu/Zn ratio), in relation to the prevalence of knee chondrocalcinosis. METHODS: Data included in this analysis were retrieved from a large population-based cross-sectional study. A bilateral knee anteroposterior radiograph was obtained from each subject. Radiographic knee chondrocalcinosis was diagnosed if definite linear cartilage calcification was detected. Serum zinc and copper concentrations were measured using the spectrophotometric flow injection methods by Roche modular P800. The relations of serum zinc and copper concentrations and Cu/Zn ratio to the prevalence of knee chondrocalcinosis were examined using generalized estimating equations, respectively. RESULTS: The prevalence of knee chondrocalcinosis was 1.2% in the sample of this study (n = 12,362). In comparison with the lowest tertile, the odds ratios (ORs) of knee chondrocalcinosis adjusted by age, sex and body mass index were 0.74 (95% CI 0.50-1.09) in the second and 0.56 (95% CI 0.36-0.86) in the third tertiles of serum zinc concentrations (P for trend = 0.009), were 1.26 (95% CI 0.77-2.05) in the second and 2.01 (95% CI 1.25-3.24) in the third tertile of serum copper concentrations (P for trend = 0.003), and were 1.02 (95% CI 0.61-1.69) in the second and 2.23 (95% CI 1.38-3.59) in the third tertile of Cu/Zn ratio (P for trend < 0.001) respectively. These findings were not materially altered by adjustment for potential confounders. CONCLUSIONS: The present study observed that higher serum zinc concentrations, lower serum copper concentrations or lower Cu/Zn ratio are associated with a lower prevalence of knee chondrocalcinosis in a dose-response relationship manner.

Crystal arthritides - gout and calcium pyrophosphate arthritis : Part 2: clinical features, diagnosis and differential diagnostics.

Gout develops in four stages beginning with an asymptomatic increase in blood levels of uric acid. An acute gout attack is an expression of an underlying inflammatory process, which in the course of time is self-limiting. Without therapy monosodium urate crystals remain in the synovial fluid and synovial membrane and trigger more acute attacks. In the course of the disease monosodium urate crystals form deposits (tophi) leading in severe forms to irreversible joint deformities with loss of functionality. In 20% of cases gout leads to involvement of the kidneys. Overproduction of uric acid can cause nephrolithiasis. These stones can be composed of uric acid or calcium phosphate. Another form of kidney disease caused by gout is uric acid nephropathy. This is a form of abacterial chronic inflammatory response with deposition of sodium urate crystals in the medullary interstitium. Acute obstructive nephropathy is relatively rare and characterized by renal failure due to uric acid precipitation in the tubules because of rapid cell lysis that occurs, for example, with chemotherapy. There is a causal interdependence between the occurrence of hyperuricemia and hypertension. Uric acid activates the renin-angiotensin-aldosterone (RAA) system and inhibits nitric oxide (NO) with the possible consequence of a rise in systemic vascular resistance or arteriolar vasculopathy; however, uric acid is also an apparently independent risk factor for atherosclerosis. In contrast to young patients, the diagnosis of an acute gout attack in the elderly can be a challenge for the physician. Polyarticular manifestations and obscure symptoms can make it difficult to differentiate it from rheumatoid arthritis and calcium pyrophosphate deposition disease (CPPD). Aspiration of synovial fluid with visualization of urate crystals using compensated polarized light microscopy is the gold standard for diagnosis of acute gout. Moreover, analysis of synovial fluid enables a distinction from septic arthritis by Gram staining and bacterial culture. Soft tissue ultrasonography is useful to detect affected synovial tissue and monosodium urate crystals within the synovial fluid. Involvement of bone occurs relatively late in the disease so that x­ray images are not useful in the early stages but might be helpful in differential diagnostics. Dual energy computed tomography (CT) and magnetic resonance imaging (MRI) can be used for certain indications.

Crystal arthritides - gout and calcium pyrophosphate arthritis : Part 1: Epidemiology and pathophysiology.

Gout and calcium pyrophosphate deposition disease (CPPD, pseudogout) are still the most frequent inflammatory arthritides in multimorbid elderly patients. Gout and CPPD are different diseases and based on different pathophysiological principles. Gout is closely associated with the metabolic syndrome and is an independent risk factor for cardiovascular mortality. The prevalence of asymptomatic hyperuricemia is estimated to be 10-20% of adults in industrial nations and prevalence is strongly associated with age. More than 7% of persons aged over 65 years suffer from clinically manifest gout. The underlying pathophysiological principle is an imbalance between the formation and elimination of uric acid. The degradation of the purine bases adenine and guanosine to uric acid is catalysed by xanthine oxidase and genetic polymorphisms and mutations play an important role in absorption and excretion processes. Furthermore, carrier proteins, such as URAT-1 or OAT-4 also have an influence on these processes. An imbalance of the physiological processes results in the solubility product being exceeded, which in consequence leads to crystallization of urate. This induces a cascade of massive inflammatory reactions at the molecular and cellular level with the activation of cytokines. The inflammatory process can be stopped by neutrophil extracellular traps (NETs) that modulate aggregation and degradation of chemokines and cytokines and partitioning of crystallized urate against immune cells. Calcium pyrophosphate dehydrate (CPP) crystals are formed in the cartilage and CPP deposition can be found in 30% of people aged over 80 years. Inorganic pyrophosphate (PPi) is synthesized in chondrocytes and plays an important part in the formation of calcium pyrophosphate crystals. The degradation is catalyzed by inorganic pyrophosphatases. If there is dysregulation of this homeostasis more PPi is produced, which ultimately contributes to the formation of the CPP crystals.

Mineral and Bone Disorder in Chronic Kidney Disease: A Case Report from Vietnam.

We report a case of calcium pyrophosphate dihydrate deposition disease (CPDD) involving a patient on maintenance hemodialysis (MHD). The 32-year-old man presented in August 2016 with a complaint of left shoulder swelling of 8 months' duration with no trauma or fever. He was diagnosed with nephrotic syndrome in 1998, which progressed to ESRD. He commenced MHD in 2012. Examination at our hospital revealed a soft nontender swelling of the left shoulder. Blood biochemistry showed elevated serum urate, phosphate, ß2 microglobulin, and parathyroid hormone. Imaging revealed joint effusion and dense heterogenous deposition. Aspirate analysis showed urate crystals 3+, and culture yielded no growth. Following rheumatology review, the working diagnosis was periarticular tissue tuberculosis, after excluding pseudogout and amyloidosis. Following 1 month of colchicine and allopurinol, synovial fluid microscopy showed CPDD crystals. Symptoms gradually resolved over the course of 6 months. In this rare case, a diagnosis of CPDD was made with a multidisciplinary approach that included imaging and biochemical investigations.

The Augustine blood group system, 48 years in the making.

The high-prevalence antigen, Ata, was first identified in 1967, but it was not until 2015 that Ata became AUG1 of a new blood group system, Augustine (AUG). The new system was established after the identification of the gene encoding Ata and the recognition of a null phenotype (AUG:­1,­2) in an At(a­) patient with an antibody (anti-AUG2) reactive with At(a­) red blood cells. The At(a­) phenotype is very rare and, with the exception of the one family with the null phenotype, has only been found in individuals of African origin. Anti-Ata has been implicated in immediate and delayed hemolytic transfusion reactions, but not in severe hemolytic disease of the fetus and newborn. The Augustine gene is SLC29A1, which encodes the equilibrative nucleoside transporter ENT1. At(a­) (AUG:­1,2) results from homozygosity for c.1171G>A, encoding Glu391Lys, whereas the AUGnull (AUG:­1,­2) phenotype results from homozygosity for a splice site mutation, c.589+1G>C, in the only family where it has been found. Absence of ENT1 in that family may be associated with pseudogout and abnormal bone calcification.

Gitelman syndrome disclosed by calcium pyrophosphate deposition disease: early diagnosis by ultrasonographic study.

Gitelman's syndrome is a rare autosomal-recessive tubular disorder characterized by hypomagnesemia and hypocalciuria associated to hypokalemia. The clinical spectrum is wide and usually characterized by chronic fatigue, cramps, muscle weakness and paresthesiae. We describe a case of a 43 year-old male patient with early onset of knee arthritis and no other symptoms. Ultrasound revealed diffuse and confluent hyperechoic deposits in cartilage, fibrocartilage of the menisci and synovium and calcium pyrophosphate crystals were observed in the synovial fluid of the knee. The concomitant presence of hypomagnesemia, hypocalciuria and hypokalemia made clear the diagnosis of Gitelman's syndrome associated with chondrocalcinosis.

Calcium metabolism disorders simulating rheumatologic diseases.

Hypoparathyroidism and hyperparathyroidism may lead to spondylarthropathy or spondylarthropathy-like problems and crystal arthropathy, respectively. In this report, we present 2 cases with hypoparathyroidism and 1 case with hyperparathyroidism who developed spondylarthropathy-like disease, rheumatoid arthritis-like disease, and chondrocalcinosis, respectively. We briefly discussed relationship between calcium metabolism disorders and rheumatologic manifestations. As rheumatologists, we should be always open to other diagnosis if the treatment does not work in patients with rheumatologic diseases.

Acute pseudogout - Measure serum magnesium.

We report a 49-year-old woman with an acute swollen left knee due to acute pseudogout with chondrocalcinosis as a presenting feature of Gitelman syndrome due a novel homozygous mutation of the SLC12A3 gene. This report highlights the under-recognized importance of excluding metabolic disease, including Gitelman syndrome, in younger patients whose sole presenting feature may be chondrocalcinosis with or without pseudogout, as this may impact on management and risk of further episodes. We also suggest that chondrocalcinosis and hypomagnesaemia with or without hypokalaemia are diagnostic of Gitelman syndrome.

Low prevalence of knee chondrocalcinosis and its catabolic association with serum matrix metalloproteinase 3: A rural Japanese population study.

AIM: This study aimed to elucidate the prevalence of radiographic knee chondrocalcinosis (CC) and to clarify whether CC is correlated with self-reported knee symptoms and a serum catabolic biomarker. METHODS: A total of 1278 volunteers participated. Plain radiographs of both knees were obtained. Identification of a linear calcification in the knee joint space was defined as CC. Patients with a Kellgren-Lawrence grade of 2 or more were considered to have knee osteoarthritis (OA). Symptoms were evaluated using the Knee injury and Osteoarthritis Outcome Score (KOOS) Pain scale, and serum matrix metalloproteinase-3 (MMP-3) concentration was determined. Multiple regression analysis was conducted to determine whether CC was correlated with OA, the KOOS Pain scale and MMP-3 concentration. RESULTS: Twenty-eight subjects were found to have CC (2.2%), and 389 had OA (30.4%). CC was correlated with OA (odds ratio: 5.797; P = 0.006). Additionally, CC was correlated with MMP-3 concentration (B = 11.415, ß = 0.059, P = 0.014), but not with KOOS Pain scale. CONCLUSIONS: The prevalence of CC was low in the Japanese population evaluated in this study. While CC was not correlated with self-reported knee symptoms, it was positively correlated with serum MMP-3 concentration.

Measurement of inorganic pyrophosphate in biological fluids. Elevated levels in some patients with osteoarthritis, pseudogout, acromegaly, and uremia.

A rapid and relatively simple method for measurement of inorganic pyrophosphate (PPi) in biological samples has been described. The mean +/-SEM of plasma samples from 94 normal subjects was 1.8+/-0.06 muM, giving a normal range (99% confidence limits) of 0.16 - 3.40 mumol/liter. Analysis of 17 plasma samples in duplicate showed a standard deviation of 0.18, giving a 99% probability that a single determination of plasma PPi would be +/-0.68 muM of the true value. The mean PPi levels in plasma from subjects with osteoarthritis, pseudogout, acromegaly, and uremia were significantly greater than the normal mean (P < 0.01). Samples from rheumatoid arthritis showed PPi levels distributed about a mean identical to the normal mean. Plasma inorganic orthophosphate levels correlated positively with PPi levels in samples from normal subjects and in samples from patients with osteoarthritis, pseudogout, and uremia, but not with acromegaly. This correlation was statistically significant only in the normal samples and in those from patients with osteoarthritis.

Dose-response relationship between lower serum magnesium level and higher prevalence of knee chondrocalcinosis.

BACKGROUND: The aim was to assess serum magnesium levels in relation to prevalence of knee chondrocalcinosis in two population-based Chinese studies. METHODS: Data included in this analysis consisted of two population-based cross-sectional studies, i.e., the Xiangya Hospital Health Management Center Study and the Xiangya Osteoarthritis (XO) Study I. A bilateral knee anteroposterior radiograph was obtained from each subject. Radiographic knee chondrocalcinosis was present if there was definite linear cartilage calcification. Serum magnesium concentration was measured using the chemiluminescence method. We examined the relation of serum magnesium levels to prevalence of knee chondrocalcinosis using generalized estimating equations. RESULTS: The prevalence of knee chondrocalcinosis was 1.4% in the Xiangya Hospital Health Management Center Study (n = 12,631). Compared with the lowest tertile, the age, sex and body mass index (BMI)-adjusted odds ratios (ORs) of chondrocalcinosis were 0.59 (95% CI 0.40-0.87) and 0.49 (95% CI 0.33-0.72) in the second and the third tertiles of serum magnesium, respectively (P for trend <0.001). The prevalence of knee chondrocalcinosis in the XO Study I (n = 1316) was 4.1%. The age, sex and BMI-adjusted ORs of chondrocalcinosis were 0.67 (95% CI 0.34-1.30) in the second and 0.45 (95% CI 0.21-0.94) in the third tertile of serum magnesium when compared with the lowest tertile (P for trend = 0.030). Similar results were observed in men and women in both studies. Adjusting for additional potential confounders did not change the results materially. CONCLUSIONS: Subjects with lower levels of serum magnesium, even within the normal range, had higher prevalence of knee chondrocalcinosis in a dose-response relationship manner, suggesting that magnesium may have a preventive or therapeutic potential for knee chondrocalcinosis.

Musculoskeletal manifestations of primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT) can be associated with a variety of musculoskeletal complaints, which occasionally can be the leading or presenting manifestation. In this paper, we describe the musculoskeletal manifestations observed in patients with primary hyperparathyroidism. Medical record reviews of a select population of 74 patients with primary hyperparathyroidism are seen in a rheumatology practice. Bone manifestations included back pain in 11 patients (15.2 %), generalized bone pain in 7 patients (9.7 %), rib cage/chest pain in 6 (8.3 %), pseudoclubbing in 3, and a giant cell tumor of the mandible in 2 (2.3 %) patients. Articular manifestations such as chondrocalcinosis with or without apatite deposition disease were seen in 13 (17.7 %), arthralgias in 11 (15.2 %), and non-specific synovitis in 7 (9.7 %). Muscle weakness was observed in six patients (8.3 %) and myalgias in three (4.6 %). Less common manifestations such as Achilles tendon rupture, Jaccoud-like arthropathy, sacral insufficiency fracture, arthritis associated with fever of unknown origin (FUO), meningitis, cervical cord compression, and persistent headache were observed in single patients. Musculoskeletal findings are still a frequent and important presentation in patients with primary hyperparathyroidism seen in rheumatology practice. Some of these manifestations can be quite unusual and may represent diagnostic dilemmas to the practicing rheumatologist and/or endocrinologist.

Distinguishing gouty arthritis from calcium pyrophosphate disease and other arthritides.

OBJECTIVE: Differentiating gout, calcium pyrophosphate deposition disease (CPPD), and non-crystal-related inflammatory arthropathies (non-CRA) is essential but often clinically impossible. The sonographic double contour (DC) sign may have good specificity for gout in highly specialized centers, but it can be challenging to use it to distinguish gout from cartilage hyperenhancements in CPPD. We evaluated the diagnostic value of the DC sign alone and in combination with Doppler signals and uric acid (UA) levels in patients with acute arthritis. METHODS: We retrospectively investigated 225 acutely inflamed joints and documented the presence of DC, Doppler hypervascularization, and serum UA (SUA) levels. All patients underwent synovial fluid (SF) analysis. Sensitivity, specificity, and positive predictive values were calculated, and correlation analyses and a binary regression model were used to investigate their diagnostic values. RESULTS: The sensitivity of DC sign for crystalline arthritides was 85% and specificity 80%. Its specificity for gout was 64%, for CPPD 52%. In contrast to non-CRA hypervascularization, degree 2 and 3 Doppler signals were highly associated with gout and less with CPPD (p < 0.01). The combination of DC sign with hypervascularization and elevated UA levels increased specificity for gout to more than 90% and resulted in a 7-fold increase of the likelihood of diagnosis of gout (p < 0.01), but with a loss of sensitivity (42%). CONCLUSION: The DC sign alone is suitable for predicting crystal-related arthropathies, but it cannot reliably distinguish gout from CPPD in everyday clinical routine. Combining hypervascularization and SUA levels increases the diagnostic value, leading us to propose a diagnostic algorithm.

Bartter's syndrome, hypomagnesaemia and chondrocalcinosis.

A 45-yr-old normotensive woman with hypokalaemic alkalosis and hypomagnesaemia was diagnosed as suffering from Bartter's syndrome. A diagnosis of chondrocalcinosis had been made because of arthralgia and calcifications of cartilage of the knees. The association between both diagnoses is described as well as the possible role of hypomagnesaemia as the intermediary. The effect of spironolactone on urinary excretion of magnesium in this patient with Bartter's syndrome was studied.

Pseudogout attacks after successful treatment of hyperparathyroidism.

Two patients developed pseudogout attacks during treatment for hyperparathyroidism, the first shortly after surgery and the second during medical treatment of her hypercalcaemia. From our observations in these patients and from data in the literature, we conclude that pseudogout attacks following parathyroidectomy in patients with chondrocalcinosis are caused by the decrease in the serum calcium levels and not by the major surgical procedure itself.

Serum and synovial fluid osteocalcin in rheumatic diseases.

The mechanisms involved in juxta-articular bone destruction are poorly understood. Osteocalcin or gamma-carboxyglutamic acid (GLA) protein is a small non-collagenous bone protein. It is a sensitive marker of osteoblastic bone formation. Its seric variations in the serum in such rheumatisms as rheumatoid arthritis remain unclear. Further information on local osteoblastic activity may be obtained by assaying the level of osteocalcin in the synovium. Its serum level can be evaluated by radioimmunoassay. The same method can be used in the synovial fluid. Paired serum and synovial fluid samples have been assayed from 63 patients, 33 patients with inflammatory arthritis (rheumatoid arthritis, psoriasis, chondrocalcinosis, pyogenic arthritis) and 30 patients with mechanical joint effusion (osteoarthritis, meniscal lesions). Serum levels of osteocalcin were the same in the inflammatory group (m: 8.69 +/- 0.68 ng/ml) and in the mechanical group (m: 10.2 +/- 0.67 ng/ml). In the synovial fluid, the levels of osteocalcin were significantly lower in the inflammatory group (m: 3.27 +/- 0.40 ng/ml) than in the mechanical group (m: 6.91 +/- 0.47 ng/ml). The same results were obtained with the ratio of synovial fluid osteocalcin on serum osteocalcin. There was a significant correlation between serum and synovial fluid osteocalcin and an inverse correlation between synovial fluid osteocalcin and the number of synovial fluid cells. The present study suggests that periarticular osteoblastic depression, among patients with inflammatory arthritis, is likely.

Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species.

Matrix γ-carboxyglutamate (Gla) protein (MGP) is an important local inhibitor of vascular calcification, which can undergo two post-translational modifications: vitamin K-dependent γ-glutamate carboxylation and serine phosphorylation. While carboxylation is thought to have effects upon binding of calcium-ions, phosphorylation is supposed to affect the cellular release of MGP. Since both modifications can be exerted incompletely, various MGP species can be detected in the circulation. MGP levels were measured with two commercially available competitive and two novel sandwich assays in healthy controls, in patients with rheumatic disease, aortic valve disease, and end-stage renal disease, as well as in volunteers after vitamin K supplementation (VKS) and treatment with vitamin K antagonists (VKA). Major differences were found between the MGP assays, including significantly different behaviour with regard to vascular disease and the response to VKA and VKS. The dual-antibody assay measuring non-phosphorylated, non-carboxylated MGP (dp-ucMGP) was particularly sensitive for these changes and would be suited to assess the vascular vitamin K status. We conclude that the different assays for particular circulating MGP species allows the assessment of various aspects of the MGP system.