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British Medical Journal Dec 1961
Topics: Anemia; Anemia, Hypochromic; Anemia, Sideroblastic; Genetic Diseases, X-Linked; Pyridoxine; Vitamin B 6; beta-Thalassemia
PubMed: 13905463
DOI: 10.1136/bmj.2.5269.1756 -
British Journal of Haematology Jun 2021The discovery of hepcidin has provided a solid foundation for understanding the mechanisms of systemic iron homeostasis and the aetiologies of iron disorders. Hepcidin... (Review)
Review
The discovery of hepcidin has provided a solid foundation for understanding the mechanisms of systemic iron homeostasis and the aetiologies of iron disorders. Hepcidin assures the balance of circulating and stored iron levels for multiple physiological processes including oxygen transport and erythropoiesis, while limiting the toxicity of excess iron. The liver is the major site where regulatory signals from iron, erythropoietic drive and inflammation are integrated to control hepcidin production. Pathologically, hepcidin dysregulation by genetic inactivation, ineffective erythropoiesis, or inflammation leads to diseases of iron deficiency or overload such as iron-refractory iron-deficiency anaemia, anaemia of inflammation, iron-loading anaemias and hereditary haemochromatosis. In the present review, we discuss recent insights into the molecular mechanisms governing hepcidin regulation, how these pathways are disrupted in iron disorders, and how this knowledge is being used to develop novel diagnostic and therapeutic strategies.
Topics: Anemia, Iron-Deficiency; Animals; Erythropoiesis; Hemochromatosis; Hepcidins; Humans; Liver
PubMed: 33316086
DOI: 10.1111/bjh.17252 -
Nature Jun 2015Many acute and chronic anaemias, including haemolysis, sepsis and genetic bone marrow failure diseases such as Diamond-Blackfan anaemia, are not treatable with...
Many acute and chronic anaemias, including haemolysis, sepsis and genetic bone marrow failure diseases such as Diamond-Blackfan anaemia, are not treatable with erythropoietin (Epo), because the colony-forming unit erythroid progenitors (CFU-Es) that respond to Epo are either too few in number or are not sensitive enough to Epo to maintain sufficient red blood cell production. Treatment of these anaemias requires a drug that acts at an earlier stage of red cell formation and enhances the formation of Epo-sensitive CFU-E progenitors. Recently, we showed that glucocorticoids specifically stimulate self-renewal of an early erythroid progenitor, burst-forming unit erythroid (BFU-E), and increase the production of terminally differentiated erythroid cells. Here we show that activation of the peroxisome proliferator-activated receptor α (PPAR-α) by the PPAR-α agonists GW7647 and fenofibrate synergizes with the glucocorticoid receptor (GR) to promote BFU-E self-renewal. Over time these agonists greatly increase production of mature red blood cells in cultures of both mouse fetal liver BFU-Es and mobilized human adult CD34(+) peripheral blood progenitors, with a new and effective culture system being used for the human cells that generates normal enucleated reticulocytes. Although Ppara(-/-) mice show no haematological difference from wild-type mice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPAR-α agonists facilitate recovery of wild-type but not Ppara(-/-) mice from PHZ-induced acute haemolytic anaemia. We also show that PPAR-α alleviates anaemia in a mouse model of chronic anaemia. Finally, both in control and corticosteroid-treated BFU-E cells, PPAR-α co-occupies many chromatin sites with GR; when activated by PPAR-α agonists, additional PPAR-α is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Our discovery of the role of PPAR-α agonists in stimulating self-renewal of early erythroid progenitor cells suggests that the clinically tested PPAR-α agonists we used may improve the efficacy of corticosteroids in treating Epo-resistant anaemias.
Topics: Acute Disease; Anemia; Anemia, Hemolytic; Animals; Butyrates; Cell Culture Techniques; Cells, Cultured; Chromatin; Chronic Disease; Disease Models, Animal; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Female; Fenofibrate; Glucocorticoids; Humans; Liver; Mice; PPAR alpha; Phenylhydrazines; Phenylurea Compounds; Receptors, Glucocorticoid; Signal Transduction
PubMed: 25970251
DOI: 10.1038/nature14326 -
British Journal of Haematology May 2019Congenital dyserythropoietic anaemia type I (CDA-I) is one of a heterogeneous group of inherited anaemias characterised by ineffective erythropoiesis. CDA-I is caused by... (Review)
Review
Congenital dyserythropoietic anaemia type I (CDA-I) is one of a heterogeneous group of inherited anaemias characterised by ineffective erythropoiesis. CDA-I is caused by bi-allelic mutations in either CDAN1 or C15orf41 and, to date, 56 causative mutations have been documented. The diagnostic pathway is reviewed and the utility of genetic testing in reducing the time taken to reach an accurate molecular diagnosis and avoiding bone marrow aspiration, where possible, is described. The management of CDA-I patients is discussed, highlighting both general and specific measures which impact on disease progression. The use of interferon alpha and careful management of iron overload are reviewed and suggest the most favourable outcomes are achieved when CDA-I patients are managed with a holistic and multidisciplinary approach. Finally, the current understanding of the molecular and cellular pathogenesis of CDA-I is presented, highlighting critical questions likely to lead to improved therapy for this disease.
Topics: Alleles; Anemia, Dyserythropoietic, Congenital; Genetic Testing; Glycoproteins; Humans; Interferon-alpha; Iron Overload; Mutation; Nuclear Proteins
PubMed: 30836435
DOI: 10.1111/bjh.15817 -
Ugeskrift For Laeger Oct 2022This review aims to make clinicians aware of the newly described syndrome, VEXAS. VEXAS should become an obvious differential diagnosis in cases of unexplained... (Review)
Review
This review aims to make clinicians aware of the newly described syndrome, VEXAS. VEXAS should become an obvious differential diagnosis in cases of unexplained inflammation, anemia, and rheumatological and/or hematological manifestations. Patients with VEXAS are typically male aged > 60, with inflammation, and macrocytic anaemia. On suspicion of cancer or infections patients have frequently been exposed to extensive diagnostic procedures and hospital admissions. In this review, we summarise the current knowledge of VEXAS regarding pathogenesis, symptoms, diagnosis, and treatment.
Topics: Anemia; Anemia, Macrocytic; Diagnosis, Differential; Humans; Inflammation; Male; Syndrome
PubMed: 36205150
DOI: No ID Found -
British Journal of Anaesthesia Feb 2023The Centre for Perioperative Care (CPOC) has published in September 2022 guidance addressing perioperative anaemia. This editorial addresses the definition of anaemia...
The Centre for Perioperative Care (CPOC) has published in September 2022 guidance addressing perioperative anaemia. This editorial addresses the definition of anaemia for women and management of borderline anaemia in women. We also address implications of the CPOC guidance for anaesthetists and the future direction of anaemia research and management.
Topics: Humans; Female; Blood Transfusion; Anemia; Perioperative Care; Anesthesia
PubMed: 36593165
DOI: 10.1016/j.bja.2022.11.009 -
British Journal of Anaesthesia Dec 2011Summary While complex physiological mechanisms exist to regulate and optimize tissue oxygenation under various conditions, clinical and experimental evidence indicates... (Review)
Review
Summary While complex physiological mechanisms exist to regulate and optimize tissue oxygenation under various conditions, clinical and experimental evidence indicates that anaemia, unchecked, is associated with organ injury and unfavourable outcomes. More data (especially from human studies) are needed to answer questions regarding the optimal approaches to the treatment of acute and chronic anaemia. Meantime, allogeneic blood transfusions remain the most common treatment, particularly in surgical/trauma patients and those with moderate-to-severe anaemia. Clinical studies emphasize the paradox that both anaemia and transfusion are associated with organ injury and increased morbidity and mortality across a wide span of disease states and surgical interventions. Further characterization of the mechanisms of injury is needed to appropriately balance these risks and to develop novel treatment strategies that will improve patient outcomes. Here, we present the current understanding of the physiological mechanisms of tissue oxygen delivery, utilization, adaptation, and survival in the face of anaemia and current evidence on the independent (and often, synergistic) deleterious impact of anaemia and transfusion on patient outcomes. The risks of anaemia and transfusion in the light of substantial variations in transfusion practices, increasing costs, shrinking pool of donated resources, and ambiguity about actual clinical benefits of banked allogeneic blood demand better management strategies targeted at improving patient outcomes.
Topics: Anemia; Blood Transfusion; Hospital Mortality; Humans; Length of Stay; Multiple Organ Failure; Risk Factors; Transfusion Reaction
PubMed: 22156270
DOI: 10.1093/bja/aer350 -
British Journal of Haematology Feb 2016The definition 'iron loading anaemias' encompasses a group of inherited and acquired anaemias characterized by ineffective erythropoiesis, low hepcidin levels, excessive... (Review)
Review
The definition 'iron loading anaemias' encompasses a group of inherited and acquired anaemias characterized by ineffective erythropoiesis, low hepcidin levels, excessive iron absorption and secondary iron overload. Non-transfusion-dependent β-thalassaemia is the paradigmatic example of these conditions that include dyserythropoietic and sideroblastic anaemias and some forms of myelodysplasia. Interrupting the vicious cycle between ineffective erythropoiesis and iron overload may be of therapeutic benefit in all these diseases. Induction of iron restriction by means of transferrin infusions, minihepcidins or manipulation of the hepcidin pathway prevents iron overload, redistributes iron from parenchymal cells to macrophage stores and partially controls anaemia in β-thalassaemic mice. Inhibition of ineffective erythropoiesis by activin ligand traps improves anaemia and iron overload in the same models. Targeting iron loading or ineffective erythropoiesis shows promise in preclinical studies; activin ligand traps are in clinical trials with promising results and may be useful in patients with ineffective erythropoiesis.
Topics: Activins; Anemia; Animals; Erythropoiesis; Hematinics; Hepcidins; Humans; Iron; Iron Overload; Mice; beta-Thalassemia
PubMed: 26491866
DOI: 10.1111/bjh.13820 -
The British Journal of Nutrition Feb 2023Despite several efforts by the Government of India, the national burden of anaemia remains high and its growing prevalence (between 2015-2016 and 2019-2021) is... (Review)
Review
Despite several efforts by the Government of India, the national burden of anaemia remains high and its growing prevalence (between 2015-2016 and 2019-2021) is concerning to India's public health system. This article reviews existing food-based and clinical strategies to mitigate the anaemia burden and why they are premature and insufficient. In a context where multiple anaemia control programmes are in play, this article proposes a threefold strategy for consideration. First, except the Comprehensive National Nutrition Survey, 2016-2018, which measured Hb concentration among children and adolescents aged 1-19 years using venous blood samples, all national surveys use capillary blood samples to determine Hb levels, which could be erroneous. The Indian government should prioritise conducting a nationwide survey for estimating the burden of anaemia and its clinical determinants for all age groups using venous blood samples. Second, without deciding the appropriate dose of Fe needed for an individual, food fortification programmes that are often compounded with layering of other micronutrients could be harmful and further research on this issue is needed. Same is true for the pharmacological intervention of Fe tablet or syrup supplementation programmes, which is given to individuals without assessing its need. In addition, there is a dire need for robust research to understand both the long-term benefit and side effects of Fe supplementation programmes. Third and final, the WHO is in process of reviewing the Hb threshold for defining anaemia, therefore the introduction of new anaemia control programmes should be restrained.
Topics: Child; Adolescent; Humans; Food, Fortified; Anemia; Micronutrients; Nutritional Status; India; Anemia, Iron-Deficiency; Dietary Supplements
PubMed: 35383547
DOI: 10.1017/S0007114522000927 -
Orphanet Journal of Rare Diseases Oct 2021Congenital hemolytic anemias (CHAs) comprise defects of the erythrocyte membrane proteins and of red blood cell enzymes metabolism, along with alterations of... (Review)
Review
Congenital hemolytic anemias (CHAs) comprise defects of the erythrocyte membrane proteins and of red blood cell enzymes metabolism, along with alterations of erythropoiesis. These rare and heterogeneous conditions may generate several difficulties from the diagnostic point of view. Membrane defects include hereditary spherocytosis and elliptocytosis, and the group of hereditary stomatocytosis; glucose-6-phosphate dehydrogenase and pyruvate kinase, are the most common enzyme deficiencies. Among ultra-rare forms, it is worth reminding other enzyme defects (glucosephosphate isomerase, phosphofructokinase, adenylate kinase, triosephosphate isomerase, phosphoglycerate kinase, hexokinase, and pyrimidine 5'-nucleotidase), and congenital dyserythropoietic anemias. Family history, clinical findings (anemia, hemolysis, splenomegaly, gallstones, and iron overload), red cells morphology, and biochemical tests are well recognized diagnostic tools. Molecular findings are increasingly used, particularly in recessive and de novo cases, and may be fundamental in unraveling the diagnosis. Notably, several confounders may further challenge the diagnostic workup, including concomitant blood loss, nutrients deficiency, alterations of hemolytic markers due to other causes (alloimmunization, infectious agents, rare metabolic disorders), coexistence of other hemolytic disorders (autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, etc.). Additional factors to be considered are the possible association with bone marrow, renal or hepatic diseases, other causes of iron overload (hereditary hemochromatosis, hemoglobinopathies, metabolic diseases), and the presence of extra-hematological signs/symptoms. In this review we provide some instructive clinical vignettes that highlight the difficulties and confounders encountered in the diagnosis and clinical management of CHAs.
Topics: Anemia, Hemolytic, Congenital; Erythrocytes; Hemoglobinopathies; Humans; Pyruvate Kinase; Spherocytosis, Hereditary
PubMed: 34627331
DOI: 10.1186/s13023-021-02036-4