Sarcoidosis-induced pericarditis in a patient with portopulmonary hypertension: a case report

Portopulmonary hypertension is a rare and severe complication of patients with cirrhosis. Sarcoidosis, a disease of unknown etiology, is also a cause of pulonary hypertension and right heart dysfunction. We report the case of a 51-year-old male patient, suffering from cirrhosis due to Wilson’s disease, portal hypertension and pulmonary hypertension (PH), who developed severe pericarditis. Wilson’s disease was diagnosed 8 years before his last admission to our hospital and was being successfully treated with D-penicillamine. PH was recognized 2 years before admission and being treated with bosentan. The patient complained for dyspnea at rest and the 2D echocardiogram revealed a significant amount of pericardial fluid. All other causes of acute pericarditis were excluded and his laboratory, imaging and histopathological investigation showed evidence of sarcoidosis. He underwent a therapy with corticosteroids (methylprednisolone) and his follow-up examination showed remarkable decrease of the levels of mean pulmonary artery pressure and pericardial fluid

Normal bone turnover markers in a patient with active Paget’s disease of bone: response to treatment with zoledronic acid

Celem leczenia choroby kości Pageta (PDB) jest zahamowanie zwiększonego obrotu kostnego. Obecnie lekami z wyboru są bisfosfoniany. Do wskazań do stosowania leków antyresorpcyjnych u pacjentów z objawowa postacią PDB należą: bóle kostne i stawowe, powikłania neurologiczne, planowany zabieg chirurgiczny w rejonie aktywnych zmian chorobowych i hiperkalcemia spowodowana unieruchomieniem. Celem terapii antyresorpcyjnej jest uzyskanie poprawy stanu klinicznego i remisji biochemicznej, ocenianej na podstawie normalizacji stężeń biomarkerów obrotu kostnego. Przed podjęciem decyzji o wdrożeniu terapii u chorych w późnej, sklerotycznej fazie choroby (burned out) należy wziąć pod uwagę pogorszenie stanu klinicznego, a zwłaszcza występowanie bólów kostnych. U tych chorych duże znaczenie ma badanie scyntygraficzne kości, ponieważ może ono uwidocznić zwiększoną aktywność osteoblastyczną, której mogą nie wykazać markery obrotu kostnego. W niniejszej pracy przedstawiono przypadek chorego w późnym, sklerotycznym stadium PDB, u którego występowały nasilone objawy kliniczne, lecz stężenia markerów obrotu kostnego były prawidłowe. Po leczeniu kwasem zoledronowym nastąpiła istotna poprawa kliniczna.The treatment of Paget’s disease of bone (PDB) aims at the suppression of abnormal bone turnover; bisphosphonates are currently the treatment of choice. Indications for antiresorptive treatment in symptomatic patients with PDB include bone or joint pain, neurological complications, surgery planned at an active pagetic site and hypercalcaemia from immobilisation. The goals of antiresorptive treatment are clinical improvement and biochemical remission, as assessed by the normalisation of bone turnover markers. Clinical deterioration, especially bone pain, should be considered before deciding to treat patients with late sclerotic (burned-out) PDB. Bone scintigraphy may be of importance in these patients, because it depicts increased osteoblastic activity, when bone markers may not. We present a case of late sclerotic PDB with clinical deterioration but normal bone turnover markers, who experienced significant clinical improvement after treatment with zoledronic acid

Current and emerging osteoporosis pharmacotherapy for women: state of the art therapies for preventing bone loss.

INTRODUCTION: Pharmacological options to address the imbalance between bone resorption and accrual in osteoporosis include anti-resorptive and osteoanabolic agents. Unique biologic pathways such as the Wnt/β-catenin pathway have been targeted in the quest for new emerging therapeutic strategies. Areas covered: This review provides an overview of existing pharmacotherapy for osteoporosis in women and explore state-of-the-art and emerging therapies to prevent bone loss, with an emphasis on the mechanism of action, indications and side effects. Expert opinion: Bisphosphonates appear to be a reliable and cost-effective option, whereas denosumab has introduced a simpler dosing regimen and may achieve a linear increase in bone mineral density (BMD) with no plateau being observed, along with continuous anti-fracture efficacy. Abaloparatide, a parathyroid-hormone-related peptide (PTHrP)-analogue, approved by the FDA in April 2017, constitutes the first new anabolic osteoporosis drug in the US for nearly 15 years and has also proven its anti-fracture efficacy. Romosozumab, a sclerostin inhibitor, which induces bone formation and suppresses bone resorption, has also been developed and shown a significant reduction in fracture incidence; however, concerns have arisen with regard to increased cardiovascular risk

Menopausal hormone therapy and women's health:An umbrella review

Background: There remains uncertainty about the impact of menopausal hormone therapy (MHT) on women’s health. A systematic, comprehensive assessment of the effects on multiple outcomes is lacking. We conducted an umbrella review to comprehensively summarize evidence on the benefits and harms of MHT across diverse health outcomes. Methods and findings: We searched MEDLINE, EMBASE, and 10 other databases from inception to November 26, 2017, updated on December 17, 2020, to identify systematic reviews or meta-analyses of randomized controlled trials (RCTs) and observational studies investigating effects of MHT, including estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT), in perimenopausal or postmenopausal women in all countries and settings. All health outcomes in previous systematic reviews were included, including menopausal symptoms, surrogate endpoints, biomarkers, various morbidity outcomes, and mortality. Two investigators independently extracted data and assessed methodological quality of systematic reviews using the updated 16-item AMSTAR 2 instrument. Random-effects robust variance estimation was used to combine effect estimates, and 95% prediction intervals (PIs) were calculated whenever possible. We used the term MHT to encompass ET and EPT, and results are presented for MHT for each outcome, unless otherwise indicated. Sixty systematic reviews were included, involving 102 meta-analyses of RCTs and 38 of observational studies, with 102 unique outcomes. The overall quality of included systematic reviews was moderate to poor. In meta-analyses of RCTs, MHT was beneficial for vasomotor symptoms (frequency: 9 trials, 1,104 women, risk ratio [RR] 0.43, 95% CI 0.33 to 0.57, p [less than] 0.001; severity: 7 trials, 503 women, RR 0.29, 95% CI 0.17 to 0.50, p = 0.002) and all fracture (30 trials, 43,188 women, RR 0.72, 95% CI 0.62 to 0.84, p = 0.002, 95% PI 0.58 to 0.87), as well as vaginal atrophy (intravaginal ET), sexual function, vertebral and nonvertebral fracture, diabetes mellitus, cardiovascular mortality (ET), and colorectal cancer (EPT), but harmful for stroke (17 trials, 37,272 women, RR 1.17, 95% CI 1.05 to 1.29, p = 0.027) and venous thromboembolism (23 trials, 42,292 women, RR 1.60, 95% CI 0.99 to 2.58, p = 0.052, 95% PI 1.03 to 2.99), as well as cardiovascular disease incidence and recurrence, cerebrovascular disease, nonfatal stroke, deep vein thrombosis, gallbladder disease requiring surgery, and lung cancer mortality (EPT). In meta-analyses of observational studies, MHT was associated with decreased risks of cataract, glioma, and esophageal, gastric, and colorectal cancer, but increased risks of pulmonary embolism, cholelithiasis, asthma, meningioma, and thyroid, breast, and ovarian cancer. ET and EPT had opposite effects for endometrial cancer, endometrial hyperplasia, and Alzheimer disease. The major limitations include the inability to address the varying effects of MHT by type, dose, formulation, duration of use, route of administration, and age of initiation and to take into account the quality of individual studies included in the systematic reviews. The study protocol is publicly available on PROSPERO (CRD42017083412). Conclusions: MHT has a complex balance of benefits and harms on multiple health outcomes. Some effects differ qualitatively between ET and EPT. The quality of available evidence is only moderate to poor

Menopause and diabetes : EMAS clinical guide

Introduction: Whether menopause increases the risk of type 2 diabetes mellitus (T2DM) independently of ageing has been a matter of debate. Controversy also exists about the benefits and risks of menopausal hormone therapy (MHT) in women with T2DM. Aims: To summarise the evidence on 1) the effect of menopause on metabolic parameters and the risk of T2DM, 2) the effect of T2DM on age at menopause, 3) the effect of MHT on the risk of T2DM, and 4) the management of postmenopausal women with T2DM. Materials and methods: Literature review and consensus of experts' opinions. Results and conclusion: Metabolic changes during the menopausal transition include an increase in and the central redistribution of adipose tissue, as well as a decrease in energy expenditure. In addition, there is impairment of insulin secretion and insulin sensitivity and an increase in the risk of T2DM. MHT has a favourable effect on glucose metabolism, both in women with and in women without T2DM, while it may delay the onset of T2DM. MHT in women with T2DM should be administered according to their risk of cardiovascular disease (CVD). In women with T2DM and low CVD risk, oral oestrogens may be preferred, while transdermal 17 beta-oestradiol is preferred for women with T2DM and coexistent CVD risk factors, such as obesity. In any case, a progestogen with neutral effects on glucose metabolism should be used, such as progesterone, dydrogesterone or transdermal norethisterone. Postmenopausal women with T2DM should be managed primarily with lifestyle intervention, including diet and exercise. Most of them will eventually require pharmacological therapy. The selection of antidiabetic medications should be based on the patient's specific characteristics and comorbidities, as well on the metabolic, cardiovascular and bone effects of the medications.Peer reviewe

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

The genetic history of the Southern Arc: a bridge between West Asia and Europe

By sequencing 727 ancient individuals from the Southern Arc (Anatolia and its neighbors in Southeastern Europe and West Asia) over 10,000 years, we contextualize its Chalcolithic period and Bronze Age (about 5000 to 1000 BCE), when extensive gene flow entangled it with the Eurasian steppe. Two streams of migration transmitted Caucasus and Anatolian/Levantine ancestry northward, and the Yamnaya pastoralists, formed on the steppe, then spread southward into the Balkans and across the Caucasus into Armenia, where they left numerous patrilineal descendants. Anatolia was transformed by intra–West Asian gene flow, with negligible impact of the later Yamnaya migrations. This contrasts with all other regions where Indo-European languages were spoken, suggesting that the homeland of the Indo-Anatolian language family was in West Asia, with only secondary dispersals of non-Anatolian Indo-Europeans from the steppe

Study of bone disease in patients with haemophilia

Background: Haemophilia A and B are X-linked recessive bleedingdisorders characterized by deficiency of factor VIII and IX respectively,which leads to spontaneous intra-articular bleeding episodes (haemophilicarthropathy). Reduced mobility due to haemophilic arthropathy andavoidance of weight-bearing exercise negatively affect the acquisition ofpeak bone mass and may increase bone resorption in adult life.Few studies have assessed the prevalence of bone disease in haemophiliacs.No study has so far evaluated the effects of anti-osteoporotic therapy onBMD in these patients.Aim: The primary end-point of this prospective study was to estimate theprevalence of low BMD in haemophiliacs and its association with potentialrisk factors.The secondary endpoint was to estimate the effect of 12-month therapy oforal ibandronate on BMD and bone turnover markers (BTM) in patients atincreased risk for fracture.Patients and Methods: Adult patients with haemophilia A and B followedupin the Haemophilia Centre of Northern Greece were included. Thefollowing markers of bone resorption were measured: serum N- (NTX) andC-terminal telopeptide of type 1 collagen (CTX) and tartrate-resistant acidphosphatase band 5b (TRAP-5b). Bone formation was assessed byosteocalcin (OC) and bone-specific alkaline phosphatase (b-ALP).Adult patients with T-score <-2.5 SD or Z-score <-2 SD and/or increasedrisk of fracture received ibandronate 150mg/month, along with calciumcarbonate 1000 mg/d and cholecalciferol 800 IU/d.Results: One-hundred and four male patients (aged 45.8±15.1 years) and 50controls (aged 44.9±12.8 years) were screened. Low BMD was diagnosedin 28 patients (26.9%) and 10 controls (20%) (p=0.0001). BMD waspositively associated with the severity of haemophilia, history of HCV orHI, level of physical activity and 25-hydroxyvitamin D [25(OH)D], andnegatively with the level of arthropathy and the number of affected joints.In multiple-regression analysis, only the level of physical activity and25(OH)D concentrations significantly predicted BMDThe estimated 10-year risk for major osteoporotic fracture and hip fracturewas greater in those with low BMD (4.9±4.1% vs 2.6±1.8%, p=0.026 and2.4±3.3% vs 0.45±0.64, p=0.002, respectively). Patients with low BMD hadsignificantly lower levels of b-ALP compared with those with normalBMD. The differences between the 2 groups regarding the other 4 BTMwere not significant. A negative association between CTX and b-ALP levels with hip BMD andbetween ΝΤΧ and estradiol levels was observed. NTX and TRAP-5b levelswere positively associated with HIV infection, number of affected jointsand arthropathy scores.In patients with low BMD, NTX, TRAP-5b and b-ALP levels werepositively correlated with the number of affected joints and arthropathyscores (TRAP-5b) and negatively with physical activity score. The negativeassociation of NTX, as well as CTX, with estradiol levels was alsoobserved.Ten patients (mean age 43.5±13.5 years) received ibandronate. Ibandronatetherapy resulted in an increase in lumbar BMD (from 0.886±0.169 to0.927±0.176 g/cm2, 4.7%, p=0.004), without any change in total hip andneck BMD. Ibandronate led to a significant decrease in CTX (from0.520±0.243 to 0.347±0.230 ng/ml, -29.9%, p=0.042), without any changeother BTM.Conclusions: Our study showed increased prevalence of low BMD inhaemophiliacs. The levels of physical activity and 25(OH)D independentlypredicted low BMD.Increased bone metabolism exists in haemophiliacs with low BMD.Arthropathy, low physical activity, HIV infection and low estradiol levelsare associated with increased bone resoption, which may contribute to thepathogenesis of low bone mass in those patients.Ibandronate significantly improved lumbar BMD and reduced boneresorption, although its effect on hip BMD and bone formation was notsignificant.ΕΙΣΑΓΩΓΗ: Η αιμορροφιλία Α και Β αποτελούν κληρονομικέςδιαταραχές της πήξης του αίματος που χαρακτηρίζονται από ανεπάρκειατων παραγόντων VIII και IX, αντίστοιχα, η οποία οδηγεί σε αυτόματεςενδοαρθρικές αιμορραγίες (αιμορροφιλική αρθροπάθεια). Η μειωμένηκινητικότητα λόγω της αιμορροφιλικής αρθροπάθειας και η αποφυγήασκήσεων άρσης-βάρους επιδρούν αρνητικά στην απόκτηση κορυφαίαςοστικής πυκνότητας και αυξάνουν την οστική απορρόφηση στην ενήλικοζωή.Λίγες μελέτες υπάρχουν σχετικά με την επίπτωση της χαμηλής οστικήςπυκνότητας (BMD) στους αιμορροφιλικούς. Δεν υπάρχει μέχρι στιγμήςμελέτη εκτίμησης της επίδρασης της αντι-οστεοπορωτικής αγωγής στηBMD στους ασθενείς αυτούς.ΣΚΟΠΟΙ: Πρωτογενής σκοπός της μελέτης ήταν να εκτιμήσει τηνεπίπτωση της χαμηλής BMD στους ασθενείς με αιμορροφιλία Α και Β καιτη συσχέτισή της με πιθανούς παράγοντες κινδύνου.Δευτερογενής σκοπός ήταν η εκτίμηση της επίδρασης της 12μηνηςθεραπείας με ιμπανδρονάτη στη BMD και τους δείκτες οστικούμεταβολισμού (ΔΟΜ) στους ασθενείς με αυξημένο κίνδυνο κατάγματος.ΑΣΘΕΝΕΙΣ-ΜΕΘΟΔΟΙ: Στη μελέτη έλαβαν μέρος ενήλικες ασθενείς μεαιμορροφιλία Α και Β που παρακολουθούνται στο αιμορροφιλικό κέντροΒορείου Ελλάδας.Μετρήθηκαν οι κάτωθι δείκτες οστικού καταβολισμού: ΝΤΧ, CTX, TRAP-5b, ενώ ο οστικός σχηματισμός εκτιμήθηκε με τη μέτρηση της OC και τηςb-ALP.Στους ασθενείς με T-score <-2,5 SD ή Z-score <-2 και/ή αυξημένοκαταγματικό κίνδυνο βάσει του μοντέλου FRAX χορηγήθηκειμπανδρονάτη 150mg/μήνα, σε συνδυασμό με 1000 mg/ημέρα ασβεστίουκαι 800 IU/ημέρα χοληκαλσιφερόλης.ΑΠΟΤΕΛΕΣΜΑΤΑ: Εκατόν-τέσσερις άρρενες ασθενείς (μέσης ηλικίας45,8±15,1 έτη) και 50 υγιείς μάρτυρες (μέσης ηλικίας 44,9±12,8 έτη)συμπεριλήφθησαν. Χαμηλή BMD παρατηρήθηκε σε 28 ασθενείς (26,9%)και 10 μάρτυρες (20%) (p=0,0001). Η BMD συσχετίστηκε θετικά με τηβαρύτητα της αιμορροφιλίας, το ιστορικό HCV ή HIV λοίμωξης, τοεπίπεδο φυσικής δραστηριότητας και τη συγκέντρωση της 25(ΟΗ)D, ενώυπήρξε αρνητική συσχέτιση με το βαθμό αρθροπάθειας και τον αριθμό τωνπροσβεβλημένων αρθρώσεων. Μετά από έλεγχο με τη μέθοδο της πολλαπλής ιεραρχικής παλινδρόμησης,μόνο το επίπεδο της φυσικής δραστηριότητας και η συγκέντρωση της25(OH)D στον ορό προέβλεψαν σημαντικά την BMD.Ο υπολογιζόμενος 10-ετής κίνδυνος για μείζον οστεοπορωτικό κάταγμα καιγια κάταγμα ισχίου ήταν μεγαλύτερος στους ασθενείς με χαμηλή BMD(4,9±4,1% έναντι 2,6±1,8%, p=0,026 και 2,4±3,3% έναντι 0,45±0,64,p=0,002, αντίστοιχα). Οι ασθενείς με χαμηλή BMD είχαν σημαντικάυψηλότερα επίπεδα b-ALP σε σύγκριση με εκείνους με φυσιολογική BMD.Οι διαφορές μεταξύ των 2 ομάδων σχετικά με τους άλλους ΔΟΜ δεν ήτανσημαντικές.Παρατηρήθηκε αρνητική συσχέτιση των επιπέδων του CTX-Ι και της b-ALP με τη BMD ισχίου, θετική συσχέτιση του NTX-Ι και TRAP-5b με τηνπαρουσία HIV λοίμωξης, αρνητική συσχέτιση των επιπέδων του ΝΤΧ-Ι μετα επίπεδα οιστραδιόλης και θετική των επιπέδων του CTX-Ι, της TRAP-5b, της b-ALP και της OC με τον αριθμό των προσβεβλημένων αρθρώσεωνκαι το βαθμό αρθροπάθειας.Στους ασθενείς με χαμηλή BMD, τα επίπεδα των NTX, TRAP-5b και b-ALP συσχετίστηκαν θετικά με τον αριθμό των προσβεβλημένωναρθρώσεων και το βαθμό αρθροπάθειας και αρνητικά με το βαθμό τηςφυσικής δραστηριότητας Βρέθηκε επίσης αρνητική συσχέτιση τωνεπιπέδων οιστραδιόλης με τα εκείνα των ΝTX-Ι και CTX-Ι.Δέκα ενήλικες ασθενείς έλαβαν ιμπανδρονάτη. Η θεραπεία μειμπανδρονάτη οδήγησε σε αύξηση της BMD στην οσφυϊκή μοίρα τηςσπονδυλικής στήλης (ΟΜΣΣ) (από 0,886±0,169 σε 0,927±0,176 g/cm2,+4,7%, p=0,004), χωρίς σημαντική μεταβολή στο ολικό ισχίο ή τον αυχένατου μηριαίου. Οδήγησε επόσης σε σημαντική ελάττωση των επιπέδων τουCTX (από 0,520±0,243 σε 0,347±0,230 ng/ml, -29,9%, p=0,042), χωρίςαλλαγή στους υπόλοιπους ΔΟΜ.ΣΥΜΠΕΡΑΣΜΑΤΑ: Η παρούσα μελέτη έδειξε αυξημένη συχνότηταχαμηλής BMD στους αιμορροφιλικούς ασθενείς, για την οποία το επίπεδοφυσικής δραστηριότητας και τα επίπεδα της 25(OH)D αποτέλεσανανεξάρτητους προγνωστικούς δείκτες.Στους ασθενείς με χαμηλή BMD φάνηκε να υπάρχει αυξημένος οστικόςμεταβολισμός. Ο βαθμός και η έκταση της αρθροπάθειας, η χαμηλή φυσικήδραστηριότητα, η HIV λοίμωξη και τα χαμηλά επίπεδα οιστραδιόληςσχετίζονται υψηλό ρυθμό οστικής απορρόφησης, γεγονός το οποίο φαίνεταινα συμμετέχει στην παθογένεια της οστικής νόσου στους ασθενείς αυτούς.Τέλος, η χορήγηση της ιμπανδρονάτης βελτίωσε σημαντικά την BMD στηνΟΜΣΣ και επιβράδυνε το ρυθμό οστικής απορρόφησης