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Presse Medicale (Paris, France : 1983) Dec 2023Liver involvement in SCD patients is frequent but often misdiagnosed or underestimated, except in case of advanced liver diseases. Because of so far poorly recognized...
Liver involvement in SCD patients is frequent but often misdiagnosed or underestimated, except in case of advanced liver diseases. Because of so far poorly recognized forms of chronic SCD-related vascular injury that can silently evolved towards end stages or facilitate ACLF, any persisting liver function tests abnormalities should be carefully investigated, following the above proposed algorithm. Work up and management must be considered multidisciplinary in relationship with a Hepatologist. Early SCD hepatopathy should prompt revision of SCD management to prevent further liver injury and decompensation, discussing transfusion exchanges and hydro urea when not yet initiated, and control for any cofactor of liver injury. The role of HSCT in early SCD hepatopathies also deserves evaluation. In advanced SCD hepatopathies, liver transplantation, which has been rarely performed so far, is the only therapeutic option associated with improved survival. It should definitely be discussed- either electively in case of decompensation in SCD cirrhosis or jaundice/recurrent cholangitis in cholestatic diseases, with excellent outcome, - or emergently in case of ALF or ACLF with more mitigate results. To improve knowledge and management of SCD liver diseases, creation of national and international registries, as well as longitudinal observational cohorts are encouraged.
Topics: Humans; Anemia, Sickle Cell; Liver Diseases; Liver Transplantation; Liver Cirrhosis
PubMed: 37981193
DOI: 10.1016/j.lpm.2023.104212 -
International Health Nov 2023Thalassemia is a major health challenge in the United Arab Emirates (UAE), however previous studies have focused on genetics and molecular characterisation while...
Thalassemia is a major health challenge in the United Arab Emirates (UAE), however previous studies have focused on genetics and molecular characterisation while neglecting culture and society. In this commentary, we discuss how tradition and religion in the UAE (e.g. consanguinity, endogamy, illegality of abortion and in vitro fertilisation, adoption restrictions), and limited academic research, affect the prevention and management of the blood disorder. It is suggested that changing attitudes towards traditional marriage practices, education and awareness campaigns targeting families and young people, and earlier genetic testing, are culturally acceptable solutions to curbing the high incidence of thalassemia in the UAE.
Topics: Humans; Adolescent; United Arab Emirates; Thalassemia; Educational Status
PubMed: 36810680
DOI: 10.1093/inthealth/ihad011 -
Annals of the New York Academy of... Dec 2023Thalassemias are among the most common hereditary diseases in the world because heterozygosity offers protection against malarial infection. Affected individuals have... (Review)
Review
Thalassemias are among the most common hereditary diseases in the world because heterozygosity offers protection against malarial infection. Affected individuals have variable expression of alpha or beta chains that lead to their unbalanced utilization during hemoglobin formation, oxidative stress, and apoptosis of red cell precursors prior to maturation. Some individuals produce sufficient hemoglobin to survive but suffer the vascular stress imposed by chronic anemia and ineffective erythropoiesis. In other patients, mature red cell formation is insufficient, and chronic transfusions are required-suppressing anemia and ineffective erythropoiesis but at the expense of iron overload. The cardiovascular consequences of thalassemia have changed dramatically over the previous five decades because of evolving treatment practices. This review summarizes this evolution, focusing on complications and management pertinent to modern patient cohorts.
Topics: Humans; beta-Thalassemia; Longevity; Thalassemia; Hemoglobins; Heart; Iron Overload; Erythropoiesis
PubMed: 37902424
DOI: 10.1111/nyas.15078 -
Orphanet Journal of Rare Diseases May 2024Brain injury in hereditary hemoglobinopathies is commonly attributed to anemia-related relative hypoperfusion in terms of impaired oxygen blood supply. Supratentorial...
BACKGROUND
Brain injury in hereditary hemoglobinopathies is commonly attributed to anemia-related relative hypoperfusion in terms of impaired oxygen blood supply. Supratentorial and infratentorial vascular watershed regions seem to be especially vulnerable, but data are very scarce.
AIMS
We investigated a large beta-thalassemia sample with arterial spin labeling in order to characterize regional perfusion changes and their correlation with phenotype and anemia severity.
METHODS
We performed a multicenter single-scanner cross-sectional 3T-MRI study analyzing non-invasively the brain perfusion in 54 transfusion-dependent thalassemia (TDT), 23 non-transfusion-dependent thalassemia (NTDT) patients and 56 Healthy Controls (HC). Age, hemoglobin levels, and cognitive functioning were recorded.
RESULTS
Both TDT and NTDT patients showed globally increased brain perfusion values compared to healthy controls, while no difference was found between patient subgroups. Using age and sex as covariates and scaling the perfusion maps for the global cerebral blood flow, beta-thalassemia patients showed relative hyperperfusion in supratentorial/infratentorial watershed regions. Perfusion changes correlated with hemoglobin levels (p = 0.013) and were not observed in the less severely anemic patients (hemoglobin level > 9.5 g/dL). In the hyperperfused regions, white matter density was significantly decreased (p = 0.0003) in both patient subgroups vs. HC. In NTDT, white matter density changes correlated inversely with full-scale Intelligence Quotient (p = 0.007) while in TDT no correlation was found.
CONCLUSION
Relative hyperperfusion of watershed territories represents a hemodynamic hallmark of beta-thalassemia anemia challenging previous hypotheses of brain injury in hereditary anemias. A careful management of anemia severity might be crucial for preventing structural white matter changes and subsequent long-term cognitive impairment.
Topics: Humans; beta-Thalassemia; Male; Female; Adult; Magnetic Resonance Imaging; Cross-Sectional Studies; Brain; Young Adult; Cerebrovascular Circulation; Adolescent; Middle Aged; Child
PubMed: 38773534
DOI: 10.1186/s13023-024-03194-x -
Clinical Chemistry Sep 2023Oxford Nanopore Technology (ONT) third-generation sequencing (TGS) is a versatile genetic diagnostic platform. However, it is nonetheless challenging to prepare...
BACKGROUND
Oxford Nanopore Technology (ONT) third-generation sequencing (TGS) is a versatile genetic diagnostic platform. However, it is nonetheless challenging to prepare long-template libraries for long-read TGS, particularly the ONT method for analysis of hemoglobinopathy variants involving complex structures and occurring in GC-rich and/or homologous regions.
METHODS
A multiplex long PCR was designed to prepare library templates, including the whole-gene amplicons for HBA2/1, HBG2/1, HBD, and HBB, as well as the allelic amplicons for targeted deletions and special structural variations. Library construction was performed using long-PCR products, and sequencing was conducted on an Oxford Nanopore MinION instrument. Genotypes were identified based on integrative genomics viewer (IGV) plots.
RESULTS
This novel long-read TGS method distinguished all single nucleotide variants and structural variants within HBA2/1, HBG2/1, HBD, and HBB based on the whole-gene sequence reads. Targeted deletions and special structural variations were also identified according to the specific allelic reads. The result of 158 α-/β-thalassemia samples showed 100% concordance with previously known genotypes.
CONCLUSIONS
This ONT TGS method is high-throughput, which can be used for molecular screening and genetic diagnosis of hemoglobinopathies. The strategy of multiplex long PCR is an efficient strategy for library preparation, providing a practical reference for TGS assay development.
Topics: Humans; Sequence Analysis, DNA; Nanopores; Genomics; Hemoglobinopathies; Gene Library; High-Throughput Nucleotide Sequencing
PubMed: 37311260
DOI: 10.1093/clinchem/hvad073 -
Biosensors Feb 2024Hemoglobin (Hb) disorders are among the most common monogenic diseases affecting nearly 7% of the world population. Among various Hb disorders, approximately 1.5% of the...
Hemoglobin (Hb) disorders are among the most common monogenic diseases affecting nearly 7% of the world population. Among various Hb disorders, approximately 1.5% of the world population carries -thalassemia (-Thal), affecting 40,000 newborns every year. Early screening and a timely diagnosis are essential for -thalassemia patients for the prevention and management of later clinical complications. However, in Africa, Southern Europe, the Middle East, and Southeast Asia, where -thalassemia is most prevalent, the diagnosis and screening for -thalassemia are still challenging due to the cost and logistical burden of laboratory diagnostic tests. Here, we present Gazelle, which is a paper-based microchip electrophoresis platform that enables the first point-of-care diagnostic test for -thalassemia. We evaluated the accuracy of Gazelle for the -Thal screening across 372 subjects in the age range of 4-63 years at Apple Diagnostics lab in Mumbai, India. Additionally, 30 blood samples were prepared to mimic -Thal intermediate and -Thal major samples. Gazelle-detected levels of Hb A, Hb F, and Hb A demonstrated high levels of correlation with the results reported through laboratory gold standard high-performance liquid chromatography (HPLC), yielding a Pearson correlation coefficient = 0.99. This ability to obtain rapid and accurate results suggests that Gazelle may be suitable for the large-scale screening and diagnosis of -Thal.
Topics: Infant, Newborn; Humans; Animals; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; beta-Thalassemia; Antelopes; Hemoglobinopathies; Chromatography, High Pressure Liquid
PubMed: 38392002
DOI: 10.3390/bios14020083 -
Blood Cells, Molecules & Diseases Nov 2023Reaching a precise diagnosis in rare inherited anemia is extremely difficult and challenging, especially in areas with limited use of genetic studies, which makes...
BACKGROUND
Reaching a precise diagnosis in rare inherited anemia is extremely difficult and challenging, especially in areas with limited use of genetic studies, which makes undiagnosed anemia a unique clinical entity in tertiary hematology centers. In this study, we aim at plotting a stepwise diagnostic approach in children with undiagnosed anemia while identifying indications for genetic testing.
PATIENTS AND METHODS
A one-year cross-sectional study involved 44 children and adolescents with undiagnosed anemia after undergoing an initial routine panel of investigations. They were classified based on mean corpuscular volume (MCV) into 3 groups: microcytic (n = 19), normocytic (n = 14) and macrocytic (n = 11). An algorithm that included four levels of investigations was devised for each category.
RESULTS
After applying a systematic diagnostic approach, 33 patients (75 %) were diagnosed of whom 7 (15 %) had combined diagnoses, while 11 (25 %) patients remained undiagnosed. Based on the first, second, third and fourth levels of investigations, patients were diagnosed, respectively, as follows: of the 11 patients, 7 were microcytic, 3 normocytic and 1 macrocytic; of the 7 patients, 2 were microcytic, 2 normocytic, and 3 macrocytic; of 10 patients, 5 were microcytic, 4 normocytic and 1 macrocytic; finally, of the 16 patients, 8 were microcytic, 6 normocytic and 2 macrocytic. Numbers recorded appear higher than the actual number of the patients because some of them were diagnosed by more than one level of investigation. The diagnoses obtained in the microcytic group showed hemoglobinopathies, iron refractory iron deficiency anemia (IRIDA), membrane defects, sideroblastic anemia, hypo-transferrinemia, a combined diagnosis of sickle cell trait and pyropoikilocytosis. The diagnoses also showed a combined diagnosis of hereditary spherocytosis (HS) and alpha thalassemia minor, and a combined diagnosis of iron deficiency anemia and beta thalassemia minor, while 15 % remained undiagnosed. In the normocytic group, the diagnosis revealed autosomal recessive (AR) HS, vitamin B12 deficiency, pyruvate kinase deficiency (PKD), congenital dyserythropoietic anemia (CDA) type I, Diamond Blackfan anemia and beta thalassemia major. In addition, it showed a combined diagnosis of AR HS and CDA type II, a combined diagnosis of AR HS and PKD, and a combined diagnosis of dehydrated stomatocytosis (DHS) and G6PD carrier, meanwhile 20 % remained undiagnosed. Finally, the macrocytic group was diagnosed by vitamin B12 deficiency, sideroblastic anemia, PKD, a combined diagnosis of PKD and G6PD deficiency carrier, while 45 % remained undiagnosed.
CONCLUSION
Conducting a stepwise approach with different levels of investigations may help reach the diagnosis of difficult anemia without having to resort to unnecessary investigations. Combined diagnosis is an important cause of undiagnosed anemia, especially in countries with high frequency of consanguinity. The remaining 25 % of the patients continued to be undiagnosed, requiring more sophisticated investigations.
Topics: Adolescent; Humans; Child; Anemia, Iron-Deficiency; Anemia, Sideroblastic; beta-Thalassemia; Cross-Sectional Studies; Developing Countries; Vitamin B 12 Deficiency
PubMed: 37558589
DOI: 10.1016/j.bcmd.2023.102779 -
Clinical Radiology Jul 2023Sickle cell disease (SCD) is an autosomal recessive haemoglobinopathy, which manifests as multisystem ischaemia and infarction, as well as haemolytic anaemia. The... (Review)
Review
Sickle cell disease (SCD) is an autosomal recessive haemoglobinopathy, which manifests as multisystem ischaemia and infarction, as well as haemolytic anaemia. The morphological changes of red blood cells (RBCs) that promote ischaemia/infarction as the main multi-systemic manifestation, with associated vasculopathy, may also lead to haemorrhage and fat embolisation. Bone infarctions, whether of the skull or spine, are relatively common with subsequent increased infectious susceptibility. We present a broad spectrum of brain and spine imaging findings of SCD from a level III paediatric hospital in Lisbon, between 2010 and 2022. Our aim is to highlight brain and spine imaging findings from a serial review of multiple patients with SCD and respective neuroimaging characterisation.
Topics: Humans; Child; Anemia, Sickle Cell; Neuroimaging; Brain; Vascular Diseases; Head
PubMed: 36935257
DOI: 10.1016/j.crad.2023.02.013 -
Blood Feb 2024Fifty years ago, people with sickle cell disease (SCD) were discouraged from becoming pregnant, but now, most should be supported if they choose to pursue a pregnancy....
Fifty years ago, people with sickle cell disease (SCD) were discouraged from becoming pregnant, but now, most should be supported if they choose to pursue a pregnancy. They and their providers, however, should be aware of the physiological changes of pregnancy that aggravate SCD and pregnancy's unique maternal and fetal challenges. Maternal problems can arise from chronic underlying organ dysfunction such as renal disease or pulmonary hypertension; from acute complications of SCD such as acute anemia, vaso-occlusive crises, and acute chest syndrome; and/or from pregnancy-related complications such as preeclampsia, sepsis, severe anemia, thromboembolism, and the need for cesarean delivery. Fetal problems include alloimmunization, opioid exposure, fetal growth restriction, preterm delivery, and stillbirth. Before and during pregnancy, in addition to the assessment and care that every pregnant patient should receive, patients with SCD should be evaluated and treated by a multidisciplinary team with respect to their unique maternal and fetal issues.
Topics: Pregnancy; Infant, Newborn; Female; Humans; Anemia, Sickle Cell; Acute Chest Syndrome; Pregnancy Complications; Prenatal Care; Pre-Eclampsia
PubMed: 37979134
DOI: 10.1182/blood.2023020728 -
Antioxidants & Redox Signaling Jun 2024Sickle cell disease (SCD) is the most common inherited diathesis affecting mostly underserved populations globally. SCD is characterized by chronic pain and fatigue,... (Review)
Review
Sickle cell disease (SCD) is the most common inherited diathesis affecting mostly underserved populations globally. SCD is characterized by chronic pain and fatigue, severe acute painful crises requiring hospitalization and opioids, strokes, multiorgan damage, and a shortened life span. Symptoms may appear shortly after birth, and, in less developed countries, most children with SCD die before attaining age 5. Hematopoietic stem cell transplant and gene therapy offer a curative therapeutic approach, but, due to many challenges, are limited in their availability and effectiveness for a majority of persons with SCD. A critical unmet need is to develop safe and effective novel targeted therapies. A wide array of drugs currently undergoing clinical investigation hold promise for an expanded pharmacological armamentarium against SCD. Hydroxyurea, the most widely used intervention for SCD management, has improved the survival in the Western world and more recently, voxelotor (R-state-stabilizer), l-glutamine, and crizanlizumab (anti-P-selectin antibody) have been approved by the Food and Drug Administration (FDA) for use in SCD. The recent FDA approval emphasizes the need to revisit the advances in understanding the core pathophysiology of SCD to accelerate novel evidence-based strategies to treat SCD. The biomechanical breakdown of erythrocytesis, the core pathophysiology of SCD, is associated with intrinsic factors, including the composition of hemoglobin, membrane integrity, cellular volume, hydration, andoxidative stress. In this context, this review focuses on advances in emerging nongenetic interventions directed toward the therapeutic targets intrinsic to sickle red blood cells (RBCs), which can prevent impaired rheology of RBCs to impede disease progression and reduce the sequelae of comorbidities, including pain, vasculopathy, and organ damage. In addition, given the intricate pathophysiology of the disease, it is unlikely that a single pharmacotherapeutic intervention will comprehensively ameliorate the multifaceted complications associated with SCD. However, the availability of multiple drug options affords the opportunity for individualized therapeutic regimens tailored to specific SCD-related complications. Furthermore, it opens avenues for combination drug therapy, capitalizing on distinct mechanisms of action and profiles of adverse effects.
Topics: Humans; Anemia, Sickle Cell; Erythrocytes; Hydroxyurea; Animals
PubMed: 37975291
DOI: 10.1089/ars.2023.0348