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Hypophosphatasia: A Unique Disorder of Bone Mineralization.
Villa-Suárez, JM, García-Fontana, C, Andújar-Vera, F, González-Salvatierra, S, de Haro-Muñoz, T, Contreras-Bolívar, V, García-Fontana, B, Muñoz-Torres, M
International journal of molecular sciences. 2021;(9)
Abstract
Hypophosphatasia (HPP) is a rare genetic disease characterized by a decrease in the activity of tissue non-specific alkaline phosphatase (TNSALP). TNSALP is encoded by the ALPL gene, which is abundantly expressed in the skeleton, liver, kidney, and developing teeth. HPP exhibits high clinical variability largely due to the high allelic heterogeneity of the ALPL gene. HPP is characterized by multisystemic complications, although the most common clinical manifestations are those that occur in the skeleton, muscles, and teeth. These complications are mainly due to the accumulation of inorganic pyrophosphate (PPi) and pyridoxal-5'-phosphate (PLP). It has been observed that the prevalence of mild forms of the disease is more than 40 times the prevalence of severe forms. Patients with HPP present at least one mutation in the ALPL gene. However, it is known that there are other causes that lead to decreased alkaline phosphatase (ALP) levels without mutations in the ALPL gene. Although the phenotype can be correlated with the genotype in HPP, the prediction of the phenotype from the genotype cannot be made with complete certainty. The availability of a specific enzyme replacement therapy for HPP undoubtedly represents an advance in therapeutic strategy, especially in severe forms of the disease in pediatric patients.
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Threshold for calcium volume evaluation in patients with aortic valve stenosis: correlation with Agatston score.
Angelillis, M, Costa, G, De Backer, O, Mochi, V, Christou, A, Giannini, C, Spontoni, P, De Carlo, M, Søndergaard, L, Miccoli, M, et al
Journal of cardiovascular medicine (Hagerstown, Md.). 2021;(6):496-502
Abstract
BACKGROUND The evaluation of aortic valve calcium burden is important when planning for transcatheter aortic valve implantation (TAVI). Although a robust golden standard methodology is available for calcium evaluation on noncontrast-enhanced (NCE) computed tomographic (CT) series, a standard reference for calcium assessment on contrast-enhanced CT series is currently lacking. METHODS Two hundred and forty-four preprocedural CT scans from patients who had received TAVI were analysed. We correlated the aortic calcium volumes obtained on CE series at three thresholds [450, 850, and 'probe + 100' Hounsfield Units (HU)] with the Agatston score obtained on NCE scans. A subgroup analysis was performed taking into account the contrast enhancement of the left ventricular outflow tract (LVOT), with a prespecified cut-off of 300 HU. RESULTS The overall population analysis showed higher correlation with the Agatston score using the 850 HU threshold (r = 0.45, P < 0.0001); no correlation was found with the 450 HU threshold, whilst the 'probe + 100' HU threshold showed a weaker correlation (r = 0.30, P < 0.0001). In patients with LVOT enhancement less than 300 HU, 450 HU showed the highest accuracy in calcium identification (r = 0.70, P < 0.0001), whereas in patients with LVOT enhancement of at least 300 HU, the most accurate threshold was 850 HU (r = 0.46, P < 0.0001). CONCLUSION The thresholds for correct calcium identification using the automatic 3Mensio software depend on the contrast enhancement of aortic and cardiac structures, which can be estimated by measuring the HU in the LVOT. In patients with LVOT HU of less than 300, the correct threshold to be set in the software is 450 HU, whereas in patients with LVOT HU of at least 300 the correct threshold is 850 HU.
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A randomised controlled trial to examine the effects of cinacalcet on bone and cardiovascular parameters in haemodialysis patients with advanced secondary hyperparathyroidism.
Eddington, H, Chinnadurai, R, Alderson, H, Ibrahim, ST, Chrysochou, C, Green, D, Erekosima, I, Hutchison, A, Bubtana, A, Hegarty, J, et al
BMC nephrology. 2021;(1):106
Abstract
BACKGROUND Secondary hyperparathyroidism may lead to increased cardiovascular risk. The use of cinacalcet may improve bone and cardiovascular health with improved parathormone (PTH) and phosphate control. METHODS This is an open-label prospective randomised controlled trial to compare progression of cardiovascular and chronic kidney disease mineral and bone disorder (CKD-MBD) parameters. Patients were randomised to receive cinacalcet alongside standard therapy or standard therapy alone. Thirty-six haemodialysis patients who had > 90 days on dialysis, iPTH > 300 pg/mL, calcium > 2.1 mmol/L and age 18-75 years were included. Following randomization, all 36 patients underwent an intensive 12-week period of bone disease management aiming for iPTH 150-300 pg/mL. The primary outcome was change in vascular calcification using CT agatston score. Secondary outcomes included pulse wave velocity (PWV), left ventricular mass index (LVMI), carotid intima-media thickness (CIMT), augmentation index (Aix) and bone measurements. The above measurements were obtained at baseline and 12 months. RESULTS There was no evidence of a group difference in the progression of calcification (median change (IQR) cinacalcet: 488 (0 to1539); standard therapy: 563 (50 to 1214)). In a post hoc analysis combining groups there was a mean (SD) phosphate reduction of 0.3 mmol/L (0.7) and median (IQR) iPTH reduction of 380 pg/mL (- 754, 120). Regression of LVMI and CIMT was seen (P = 0.03 and P = 0.001) and was significantly associated with change of phosphate on multi-factorial analyses. CONCLUSIONS With a policy of intense CKD-MBD parameter control, no significant benefit in bone and cardiovascular markers was seen with the addition of cinacalcet to standard therapy over one year. Tight control of hyperphosphataemia and secondary hyperparathyroidism may lead to a reduction in LVMI and CIMT but this needs further investigation. Although the sample size was small, meticulous trial supervision resulted in very few protocol deviations with therapy.
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Imaging of calcific tendinopathy around the shoulder: usual and unusual presentations and common pitfalls.
Albano, D, Coppola, A, Gitto, S, Rapisarda, S, Messina, C, Sconfienza, LM
La Radiologia medica. 2021;(4):608-619
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Abstract
Rotator cuff calcific tendinopathy (RCCT) is a very common condition, characterized by calcium deposition over fibrocartilaginous metaplasia of tenocytes, mainly occurring in the supraspinatus tendon. RCCT has a typical imaging presentation: in most cases, calcific deposits appear as a dense opacity around the humeral head on conventional radiography, as hyperechoic foci with or without acoustic shadow at ultrasound and as a signal void at magnetic resonance imaging. However, radiologists have to keep in mind the possible unusual presentations of RCCT and the key imaging features to correctly differentiate RCCT from other RC conditions, such as calcific enthesopathy or RC tears. Other presentations of RCCT to be considered are intrabursal, intraosseous, and intramuscular migration of calcific deposits that may mimic infectious processes or malignancies. While intrabursal and intraosseous migration are quite common, intramuscular migration is an unusual evolution of RCCT. It is important also to know atypical regions affected by calcific tendinopathy as biceps brachii, pectoralis major, and deltoid tendons. Unusual presentations of RCCT may lead to diagnostic challenge and mistakes. The aim of this review is to illustrate the usual and unusual imaging findings of RCCT that radiologists should know to reach the correct diagnosis and to exclude other entities with the purpose of preventing further unnecessary imaging examinations or interventional procedures.
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Detecting native and bioprosthetic aortic valve disease using 18F-sodium fluoride: Clinical implications.
Fletcher, AJ, Dweck, MR
Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology. 2021;(2):481-491
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Abstract
Calcific aortic valve disease is the most common valvular disease and confers significant morbidity and mortality. There are currently no medical therapies that successfully halt or reverse the disease progression, making surgical replacement the only treatment currently available. The majority of patients will receive a bioprosthetic valve, which themselves are prone to degeneration and may also need replaced, adding to the already substantial healthcare burden of aortic stenosis. Echocardiography and computed tomography can identify late-stage manifestations of the disease process affecting native and bioprosthetic aortic valves but cannot detect or quantify early molecular changes. 18F-fluoride positron emission tomography, on the other hand, can non-invasively and sensitively assess disease activity in the valves. The current review outlines the pivotal role this novel molecular imaging technique has played in improving our understanding of native and bioprosthetic aortic valve disease, as well as providing insights into its feasibility as an important future research and clinical tool.
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Microscopic Characteristics of Late Intraocular Lens Opacifications.
Kanclerz, P, Yildirim, TM, Khoramnia, R
Archives of pathology & laboratory medicine. 2021;(6):759-767
Abstract
CONTEXT.—: The increases in overall life expectancy and in lens surgeries performed on younger patients have resulted in a significant increase in the anticipated duration of artificial intraocular lenses (IOLs) in the eye. Thus, the physicochemical properties of the IOL become a critical issue, and several types of postoperative IOL opacifications have been reported. OBJECTIVE.—: To describe the microscopic characteristics of opacified IOLs. Glistenings and subsurface nanoglistenings are fluid-related phenomena developing mainly in hydrophobic acrylic IOLs and are associated with aqueous influx into the IOL matrix. Calcification presents in hydrophilic acrylic or silicone IOLs as deposits of hydroxyapatite or other phases of calcium. Snowflake degeneration is less common, and it manifests in older polymethyl methacrylate IOLs. DATA SOURCES.—: PubMed and ScienceDirect databases were searched for the following keywords: intraocular lens, IOL, cataract surgery, phacoemulsification, opacification, glistening, subsurface nanoglistenings, calcification, snowflake degeneration. English-language articles published up to October 15, 2019 were included in the study. The manuscript contains mainly a literature review; however, it was supplemented with original investigations from the David J. Apple International Laboratory for Ocular Pathology. CONCLUSIONS.—: Glistenings and subsurface nanoglistenings should be evaluated in a hydrated state and at room temperature; they manifest as microvacuoles sized from 1.0 to greater than 25.0 μm and less than 200 nm, respectively. Calcification deposits are situated on or underneath the surface of the IOL and can be stained with a 1% alizarin red solution or with the von Kossa method. Snowflake degeneration manifests as "particles" or "crystals," causing whitish IOL discoloration. Scanning electron microscopy or energy dispersive X-ray spectroscopy may improve the diagnostic accuracy.
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Systemic sclerosis skin is a primed microenvironment for soft tissue calcification-a hypothesis.
Burgess, KA, Herrick, AL, Watson, REB
Rheumatology (Oxford, England). 2021;(6):2517-2527
Abstract
Calcinosis cutis, defined as sub-epidermal deposition of calcium salts, is a major clinical problem in patients with SSc, affecting 20-40% of patients. A number of recognized factors associated with calcinosis have been identified, including disease duration, digital ischaemia and acro-osteolysis. Yet, to date, the pathogenesis of SSc-related calcinosis remains unknown, and currently there is no effective disease-modifying pharmacotherapy. Following onset of SSc, there are marked changes in the extracellular matrix (ECM) of the skin, notably a breakdown in the microfibrillar network and accumulation of type I collagen. Our hypothesis is that these pathological changes reflect a changing cellular phenotype and result in a primed microenvironment for soft tissue calcification, with SSc fibroblasts adopting a pro-osteogenic profile, and specific driving forces promoting tissue mineralization. Considering the role of the ECM in disease progression may help elucidate the mechanism(s) behind SSc-related calcinosis and inform the development of future therapeutic interventions.
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Diagnostic Approach to Benign and Malignant Calcifications in the Abdomen and Pelvis.
Zulfiqar, M, Shetty, A, Tsai, R, Gagnon, MH, Balfe, DM, Mellnick, VM
Radiographics : a review publication of the Radiological Society of North America, Inc. 2020;(3):731-753
Abstract
Intra-abdominal calcifications are common. Multiple pathologic processes manifest within the abdomen and pelvis in association with calcifications, which can be benign, premalignant, or malignant. Although calcium deposition in the abdomen can occur secondary to various mechanisms, the most common cau se is cellular injury that leads to dystrophic calcifications. The authors provide a summary of various common and uncommon calcifications in the abdomen and pelvis, primarily using location to illuminate diagnostic significance. Six broad categories of calcifications in the abdomen and pelvis are recognized: mesenteric, peritoneal, retroperitoneal, organ-based, vascular, and musculoskeletal. In addition to site, the various patterns and morphology of calcifications encountered in various conditions can be helpful for diagnosis, especially those depicted on radiographs. For example, some patterns diagnostic for various conditions include round or oval stones in the biliary or urothelial tracts, curvilinear calcifications associated with cysts or neoplasms, and sheetlike calcifications along peritoneal surfaces in the setting of chronic peritoneal dialysis or metastatic disease. Organ encrustation with calcium may be a premalignant finding (eg, porcelain gallbladder). In addition, the development of calcium after initiation of treatment can be used as an indicator of response in conditions such as tuberculosis, lymphoma, and hydatid disease. As calcifications are almost invariably detected at imaging, it is imperative for radiologists to be aware of their diagnostic implications and use the presence of calcification in an organ, mass, or other anatomic location for problem solving. ©RSNA, 2020.
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Outcome domains reported in calcium pyrophosphate deposition studies: A scoping review by the OMERACT CPPD working group.
Cai, K, Fuller, A, Hensey, O, Grossberg, D, Christensen, R, Shea, B, Singh, JA, Abhishek, A, Tedeschi, S, Dalbeth, N
Seminars in arthritis and rheumatism. 2020;(4):719-727
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Abstract
INTRODUCTION Although calcium pyrophosphate deposition (CPPD) is common, there are no validated outcome domains and/or measurements for CPPD studies. The aim of this work was to identify domains that have been reported in prior clinical studies in CPPD, to inform the development of a core set of domains for CPPD studies. METHODS We performed a scoping literature review for clinical studies in CPPD, searching in Medline (via PubMed), EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) databases; published from January 1, 1946 to January 7, 2020. All reported outcomes and study design data were extracted and mapped to the core areas and domains as defined by the OMERACT Filter 2.1.The protocol was registered on PROSPERO (CRD: 42019137075; 09-07-2019). FINDINGS There were 112 papers identified, comprising of 109 observational studies and three randomized controlled trials. Most studies reported clinical presentations of OA with CPPD or acute CPP crystal arthritis. Outcomes that mapped to 22 domains were identified; the most frequently reported measures mapped to the following domains/sub-domains: imaging (joint damage on imaging tests - 59 studies; joint calcification on imaging tests - 28 studies), joint pain (26 studies), response to treatment (23 studies), side effects of treatment (15 studies), inflammation in the joint fluid or blood (ESR or C-reactive protein - 12 studies; synovial fluid markers - 4 studies; other blood markers - 2 studies), overall function (14 studies), joint swelling (12 studies) and range of joint movement (10 studies). Very few studies mapped to domains related to life impact, societal/resource use or longevity. CONCLUSION There is substantial variability in outcomes reported in CPPD studies. Outcomes that map to imaging manifestations, joint pain and response to treatment domains are most often reported.
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Extent of arterial calcification by conventional vitamin K antagonist treatment.
Hasific, S, Øvrehus, KA, Gerke, O, Hallas, J, Busk, M, Lambrechtsen, J, Urbonaviciene, G, Sand, NPR, Nielsen, JS, Diederichsen, L, et al
PloS one. 2020;(10):e0241450
Abstract
BACKGROUND AND AIMS Vitamin K antagonists (VKA) remain the most frequently prescribed oral anticoagulants worldwide despite the introduction of non-vitamin K antagonist oral anticoagulants (NOAC). VKA interfere with the regeneration of Vitamin K1 and K2, essential to the activation of coagulation factors and activation of matrix-Gla protein, a strong inhibitor of arterial calcifications. This study aimed to clarify whether VKA treatment was associated with the extent of coronary artery calcification (CAC) in a population with no prior cardiovascular disease (CVD). METHODS We collected data on cardiovascular risk factors and CAC scores from cardiac CT scans performed as part of clinical examinations (n = 9,672) or research studies (n = 14,166) in the period 2007-2017. Data on use of anticoagulation were obtained from the Danish National Health Service Prescription Database. The association between duration of anticoagulation and categorized CAC score (0, 1-99, 100-399, ≥400) was investigated by ordered logistic regression adjusting for covariates. RESULTS The final study population consisted of 17,254 participants with no prior CVD, of whom 1,748 and 1,144 had been treated with VKA or NOAC, respectively. A longer duration of VKA treatment was associated with higher CAC categories. For each year of VKA treatment, the odds of being in a higher CAC category increased (odds ratio (OR) = 1.032, 95%CI 1.009-1.057). In contrast, NOAC treatment duration was not associated with CAC category (OR = 1.002, 95%CI 0.935-1.074). There was no significant interaction between VKA treatment duration and age on CAC category. CONCLUSIONS Adjusted for cardiovascular risk factors, VKA treatment-contrary to NOAC-was associated to higher CAC category.