How I manage medical complications of beta-thalassemia in adults

The complex pathophysiology in beta-thalassemia can translate to multiple morbidities that affect every organ system. Improved survival due to advances in management meant that patients are exposed to the harmful effects of ineffective erythropoiesis, anemia and iron overload for a longer duration, and we started seeing new or more frequent complications in adult compared with younger patients. In this article, we highlight particular aspects of managing adult patients with beta-thalassemia utilizing our own experience in treating such patients. We cover both transfusion-dependent and non-transfusion-dependent forms of the disease and tackle specific morbidities of highest interest

Iron deficiency anaemia revisited

Iron deficiency anaemia is a global health concern affecting children, women and the elderly, whilst also being a common comorbidity in multiple medical conditions. The aetiology is variable and attributed to several risk factors decreasing iron intake and absorption or increasing demand and loss, with multiple aetiologies often coexisting in an individual patient. Although presenting symptoms may be nonspecific, there is emerging evidence on the detrimental effects of iron deficiency anaemia on clinical outcomes across several medical conditions. Increased awareness about the consequences and prevalence of iron deficiency anaemia can aid early detection and management. Diagnosis can be easily made by measurement of haemoglobin and serum ferritin levels, whilst in chronic inflammatory conditions, diagnosis may be more challenging and necessitates consideration of higher serum ferritin thresholds and evaluation of transferrin saturation. Oral and intravenous formulations of iron supplementation are available, and several patient and disease-related factors need to be considered before management decisions are made. This review provides recent updates and guidance on the diagnosis and management of iron deficiency anaemia in multiple clinical settings

An update on thalassemia intermedia

Thalassemia intermedia is a genetically diverse group of diseases that is the result of an imbalance in the production of the alpha and beta chains with ensuing chronic hemolysis, ineffective erythropoiesis, and iron overload. Resulting complications include bone changes, hypercoagulability, and end-organ damage due to iron overload. This decade has witnessed major breakthroughs in the management of thalassemia. In this article, we examine these novelties in therapy including iron chelation therapy, stem cell transplant, and gene therapy. Iron chelation therapy has been revolutionized with the advent of deferasirox, a once-daily oral iron chelator, that has been shown to be safe and efficacious. Gene therapy was also at the core of this revolution with the discovery of novel gene elements and viral vectors allowing for better control and improved outcomes.La thalass\ue9mie interm\ue9diaire englobe un groupe de maladies diverses r\ue9sultant d\u2019un d\ue9s\ue9quilibre entre la production des cha\ueenes alfa et b\ueata qui aboutit \ue0 une h\ue9molyse chronique, une \ue9rythropo\uef\ue8se inefficace et une surcharge en fer. Les complications engendr\ue9es par cette maladie sont un changement dans la constitution des os, un \ue9tat d\u2019hypercoagulabilit\ue9, et des organes majeurs endommag\ue9s suite au surplus de fer. La derni\ue8re d\ue9cennie a vu d\u2019importantes avanc\ue9es dans le traitment de la thalass\ue9mie. Sont examin\ue9es ici les toutes derni\ue8res th\ue9rapeutiques : la ch\ue9lation du fer, la greffe de cellules souches et la th\ue9rapie g\ue9n\ue9tique. L\u2019introduction de deferasirox, un ch\ue9lateur du fer administr\ue9 une fois par jour par voie orale, a r\ue9volutionn\ue9 la ch\ue9lation du fer et s\u2019est impos\ue9 comme \ue9tant un m\ue9dicament s\ufbr et efficace. La th\ue9rapie g\ue9n\ue9tique a aussi \ue9t\ue9 une innovation charni\ue8re dans les nouveaux traitements, surtout avec la d\ue9couverte r\ue9cente d\u2019\ue9l\ue9-ments g\ue9n\ue9tiques et vecteurs viraux qui permettent un meilleur contr\uf4le et am\ue9liorent les r\ue9sultats

How I treat transfusional iron overload

Mammary organoids from adult mice produce tubules, analogous to mammary ducts in vivo, in response to hepatocyte growth factor (HGF) when cultured in collagen gels. The combination of HGF plus progestin (R5020) causes reduced tubule number and length. We hypothesized that the inhibitory effect on tubulogenesis was due to progestin-mediated alteration of HGF/c-Met signaling. Using molecular inhibitors and short hairpin RNA, it was determined that HGF activation of Ras-related C3 botulinum toxin substrate (Rac1) was required for the formation of cytoplasmic extensions, the first step of tubulogenesis, and that Rac1 activity was Src kinase (Src) and focal adhesion kinase (FAK) dependent. The highly novel finding was that R5020 reduced tubulogenesis by up-regulating and increasing extracellular laminin and \u3b16-integrin ligation to reduce activation of the Src, focal adhesion kinase, and Rac1 pathway. Receptor activator of nuclear factor-\u3baB ligand, another progesterone-induced paracrine factor, did not replicate this effect of R5020. The inhibitory effect of R5020 on tubulogenesis was likely mediated through progesterone receptor (PR) isoform A (PRA), because PRA is the predominant PR isoform expressed in the organoids, and the progestin-induced effect was prevented by the PR antagonist RU486. These results provide a plausible mechanism that explains progestin/PRA-mediated blunting of HGF-induced tubulogenesis in vitro and is proposed to be relevant to progesterone/PRA- induced side-branching in vivo during pregnancy. Copyrigh

A paradigm shift on beta-thalassaemia treatment : how will we manage this old disease with new therapies?

Beta-thalassaemia causes defective haemoglobin synthesis leading to ineffective erythropoiesis, chronic haemolytic anaemia, and subsequent clinical complications. Blood transfusion and iron chelation allow long-term disease control, and haematopoietic stem cell transplantation offers a potential cure for some patients. Nonetheless, there are still many challenges in the management of beta-thalassaemia. The main treatment option for most patients is supportive care; furthermore, the long-term efficacy and safety of current therapeutic strategies are limited and adherence is suboptimal. An increasing understanding of the underlying molecular and cellular disease mechanisms plus an awareness of limitations of current management strategies are driving research into novel therapeutic options. Here we provide an overview of the current pathophysiology, clinical manifestations, and global burden of beta-thalassaemia. We reflect on what has been achieved to date, describe the challenges associated with currently available therapy, and discuss how these issues might be addressed by novel therapeutic approaches in development

β-Thalassemia : new therapeutic modalities, genetics, complications, and quality of life

Retinoic acid (RA) is a positive regulator of P19 cell differentiation. Silencing of pre-B cell leukemia transcription factors (PBXs) expression in P19 cells (AS cells) results in a failure of these cells to differentiate to endodermal cells upon RA treatment. Chicken Ovalbumin Upstream Promoter Transcription Factor I (COUP-TFI) is an orphan member of the steroid-thyroid hormone superfamily. RA treatment of wild type P19 cells results in a dramatic increase in the expression of COUP-TFI; however, COUP-TFI mRNA levels fail to be elevated upon RA treatment of AS cells indicating that PBX expression is required for elevation in COUP-TFI expression. To study the role of COUP-TFI during RA-dependent differentiation of P19 cells, AS cells that inducibly express various levels of COUP-TFI were prepared. Exogenous expression of COUP-TFI in AS cells, in a dose-dependent fashion, leads to growth inhibition, modest cell cycle disruption, and early apoptosis. Furthermore, AS cells can overcome the blockage in RA-dependent differentiation to endodermal cells when either pharmacological levels of COUP-TFI are expressed or a combination of both the expression of physiological levels of COUP-TFI and RA treatment. Additionally, the mRNA level of several pluripotency associated genes including OCT-4, DAX-1, and SF-1 in the COUP-TFI expressing AS cells are reduced. Moreover, analysis of the expression of primary RA response genes indicates that COUP-TFI is involved in the regulatory modulation of the expression of at least two genes, CYP26A1 and HoxA1. These studies demonstrate that COUP-TFI functions as a physiologically relevant regulator during RA-mediated endodermal differentiation of P19 cells

Hyponatremia: how much attention do we pay to it?

The objective is to describe hyponatremia in patients hospitalized in geriatric (GU) and Internal medicine units (IM), its characteristics and diagnostic approach in order to improve its management and treatment. It is a retrospective study. We collected data through the informatic system of the hospital, performing statistical analysis with SmallStata14. We analyzed patients admitted during 2015 who showed hyponatremia at admission or developed it in any moment during hospitalization. On 824 patients admitted to the Geriatric (n=351) and Internal Medicine (n=473) wards during 2015 (mean age 77.5\ub114.6 yrs; 56% males), 140 patients (17%) had hyponatremia. Hyponatremia was already present at admission in the emergency unit in 49 patients (74% mild; 14% moderate and 12% severe); 10 patients had hypernatremia but developed hyponatremia thereafter. More than half of the patients was taking at least one drug or had a comorbidity possibly causing hyponatremia. 78 patients (56%) developed it during hospitalization (82% mild, 17% moderate and 1% severe). The mean sodium nadir during hospitalization was 131.8\ub12.4mEq/l. Further analyses to improve the diagnostic accuracy were performed in a minority of cases (plasmatic osmolarity has never been measured, urinary osmolarity and sodium in only 3 and 14 patients respectively). At hospital discharge 48 (34%) patients were still hyponatremic (in 79% mildly) and 71 patients were still assuming at least one drug possibly causing hyponatremia. The hyponatremia was often neglected in the letter of discharge. Hyponatremia is a common observation in GU and IM and it can be due to several causes thus guidelines for its treatment are often useless. The lack of appropriate investigations often lead to improper management. Since even mild hyponatremia has been associated with bad clinical outcomes, more attention should be given, in order to improve the management. Further studies are ongoing