RESUMO
Hyperbilirubinemia in patients with sickle cell anemia (SCA) as a result of enhanced erythrocyte destruction, lead to cholelithiasis development in a subset of patients. Evidence suggests that hyperbilirubinemia may be related to genetic variations, such as the UGT1A1 gene promoter polymorphism, which causes Gilbert syndrome (GS). Here, we aimed to determine the frequencies of UGT1A1 promoter alleles, alpha thalassemia, and ßS haplotypes and analyze their association with cholelithiasis and bilirubin levels. The UGT1A1 alleles, -3.7 kb alpha thalassemia deletion and ßS haplotypes were determined using DNA sequencing and PCR-based assays in 913 patients with SCA. The mean of total and unconjugated bilirubin and the frequency of cholelithiasis in GS patients were higher when compared to those without this condition, regardless of age (P < 0.05). Cumulative analysis demonstrated an early age-at-onset for cholelithiasis in GS genotypes (P < 0.05). Low fetal hemoglobin (HbF) levels and normal alpha thalassemia genotype were related to cholelithiasis development (P > 0.05). However, not cholelithiasis but total and unconjugated bilirubin levels were associated with ßS haplotype. These findings confirm in a large cohort that the UGT1A1 polymorphism influences cholelithiasis and hyperbilirubinemia in SCA. HbF and alpha thalassemia also appear as modulators for cholelithiasis risk.
Assuntos
Anemia Falciforme/sangue , Bilirrubina/sangue , Colelitíase/etiologia , Doença de Gilbert/sangue , Glucuronosiltransferase/fisiologia , Regiões Promotoras Genéticas/genética , Talassemia alfa/sangue , Adolescente , Adulto , Idoso , Alelos , Anemia Falciforme/complicações , Anemia Falciforme/enzimologia , Anemia Falciforme/genética , Criança , Pré-Escolar , Colelitíase/sangue , Colelitíase/genética , Feminino , Hemoglobina Fetal/análise , Genótipo , Doença de Gilbert/enzimologia , Doença de Gilbert/genética , Glucuronosiltransferase/genética , Haplótipos/genética , Hemólise , Humanos , Hiperbilirrubinemia/enzimologia , Hiperbilirrubinemia/etiologia , Hiperbilirrubinemia/genética , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Talassemia alfa/complicações , Talassemia alfa/enzimologia , Talassemia alfa/genéticaRESUMO
Alpha thalassemia and beta-globin haplotype are considered classical genetic disease modifiers in sickle cell anemia (SCA) causing clinical heterogeneity. Nevertheless, their functional impact on SCA disease emergence and progression remains elusive. To better understand the role of alpha thalassemia and beta-globin haplotype in SCA, we performed a retrospective study evaluating the clinical manifestations of 614 patients. The univariate analysis showed that the presence of alpha-thalassemia -3.7-kb mutation (αα/-α and -α/-α) decreased the risk of stroke development (p = 0.046), priapism (p = 0.033), and cholelithiasis (p = 0.021). Furthermore, the cumulative incidence of stroke (p = 0.023) and cholelithiasis (p = 0.006) was also significantly lower for patients carrying the alpha thalassemia -3.7-kb mutation. No clinical effects were associated with the beta-globin haplotype analysis, which could be explained by the relatively homogeneous haplotype composition in our cohort. Our results reinforce that alpha thalassemia can provide protective functions against hemolysis-related symptoms in SCA. Although, several genetic modifiers can impact the inflammatory state of SCA patients, the alpha thalassemia mutation remains one of the most recurrent genetic aberration and should therefore always be considered first.
Assuntos
Anemia Falciforme/complicações , Talassemia alfa/complicações , Globinas beta/genética , Adolescente , Adulto , Idoso , Anemia Falciforme/sangue , Anemia Falciforme/genética , Arteriopatias Oclusivas/epidemiologia , Arteriopatias Oclusivas/etiologia , Brasil/epidemiologia , Criança , Colelitíase/epidemiologia , Colelitíase/etiologia , Feminino , Hemoglobina Fetal/análise , Seguimentos , Haplótipos/genética , Hemólise , Humanos , Úlcera da Perna/epidemiologia , Úlcera da Perna/etiologia , Masculino , Mutação , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Resultado do Tratamento , Adulto Jovem , Talassemia alfa/sangue , Talassemia alfa/genéticaAssuntos
Elementos Facilitadores Genéticos , Hemoglobina H/genética , alfa-Globinas/genética , Talassemia alfa/genética , Adulto , Alelos , Cromatina/genética , Cromatina/ultraestrutura , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 16/ultraestrutura , Eritroblastos/patologia , Eritropoese , Feminino , Deleção de Genes , Regulação da Expressão Gênica , Genótipo , Hemoglobina E/genética , Hemoglobina H/análise , Humanos , Masculino , Linhagem , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Deleção de Sequência , Suriname/etnologia , alfa-Globinas/biossíntese , Talassemia alfa/sangue , Globinas beta/genéticaRESUMO
OBJECTIVE: To determine the prevalence of low mean corpuscular volume (MCV) in newborn infants admitted to the neonatal intensive care unit and to assess low MCV as a diagnostic test for alpha thalassemia. STUDY DESIGN: Retrospective analysis of all infants admitted to the neonatal intensive care unit between January 2010 and October 2018 for which a complete blood count was performed during the first 3 postnatal days. Infants with a low MCV were compared with those with a normal MCV. Infants with positive hemoglobin Bart (Hb Bart) were compared with those withnegative Hb Bart. Low MCV was also evaluated as a diagnostic test for alpha thalassemia. RESULTS: A total of 3851 infants (1386 preterm, 2465 term) met the inclusion criteria and 853 (22.2%) had a low MCV. A low MCV was more common in term (25%) compared with preterm infants (17.1%, P < .001). Hb Bart positive newborn screening was identified in 133 infants (3.5%). Hb Bart was positive in 11.1% of infants with low MCV compared with 1.3% with normal MCV (P < .001). The sensitivity, specificity, positive predictive value, and negative predictive value of low MCV for the diagnosis of alpha thalassemia were 71.4%, 79.6%, 11.3%, and 98.7%, respectively. CONCLUSIONS: As Hb Bart positive newborn screens were seen in only 11.1% of infants with microcytosis, further diagnostic investigation may be warranted in individual infants. Further research to correlate microcytosis with iron status in infants and mothers is needed as well as studies using DNA analysis for the evaluation of alpha thalassemia variants.
Assuntos
Índices de Eritrócitos , Hemoglobinas Anormais/análise , Talassemia alfa/sangue , Estudos de Casos e Controles , Feminino , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Masculino , Triagem Neonatal/métodos , Valor Preditivo dos Testes , Gravidez , Estudos Retrospectivos , Talassemia alfa/diagnósticoRESUMO
This study investigated the effects of hydroxyurea (HU) on hematological, biochemical and inflammatory parameters in children with sickle cell anemia (SCA) in association with ßS haplotype and α-thalassemia. We included 22 children with SCA who were followed for an average of 14.5 months. Laboratory parameters were assessed by electronic methods, and molecular analysis was investigated by PCR-RFLP and allele-specific PCR. Results showed significant increases in hemoglobin, HbF, hematocrit, MCV, MCH, glucose, HDL-C and albumin levels, as well as significant decreases in MCHC and AST levels, WBC, neutrophils, eosinophils, lymphocytes and reticulocytes, in children during HU therapy. HbF levels were positively correlated with hemoglobin, hematocrit, MCV and total protein, yet negatively correlated with MCHC, RDW, AAT and AST during HU therapy (p<0.05). Children who carried the Central African Republic haplotype, in response to HU therapy, presented significant increases in hemoglobin, hematocrit, triglycerides and uric acid levels, as well as significant decreases in MCHC, AST and direct bilirubin levels, WBC, neutrophils, eosinophils, lymphocytes and reticulocytes. Those with the Benin haplotype presented increases in HbF and albumin levels, and a reduction in platelet counts (p<0.05). Children with α-thalassemia presented decreased ALT during HU use, while those without this deletion presented increases in hemoglobin, hematocrit, MCV, MCH, HDL-C and albumin, as well as decreases in MCHC, neutrophils, lymphocytes, reticulocytes and AST (p<0.05). Hence, regardless of its use in association with ßS haplotypes or α-thalassemia, HU seems to be linked to alterations in hemolytic, inflammatory, hepatic, lipid and glycemic profiles.
Assuntos
Anemia Falciforme/sangue , Anemia Falciforme/tratamento farmacológico , Haplótipos , Hidroxiureia/administração & dosagem , Talassemia alfa/sangue , Talassemia alfa/tratamento farmacológico , Bilirrubina/sangue , Biomarcadores/sangue , Glicemia/metabolismo , Criança , Pré-Escolar , Índices de Eritrócitos , Feminino , Hemoglobina Fetal/metabolismo , Hematócrito , Humanos , Lactente , Inflamação/sangue , Inflamação/tratamento farmacológico , Contagem de Leucócitos , Masculino , Gravidez , Contagem de ReticulócitosRESUMO
BACKGROUND: There is paucity of data on the influence of alpha thalassemia on the clinical and laboratory parameters among Nigerian sickle cell anemia (SCA) patients. This study aimed to determine the prevalence of alpha thalassemia and the influence of alpha thalassemia on laboratory parameters and clinical manifestations in a group of young Nigerian SCA patients. METHODS: This was a cross-sectional retrospective study conducted on 100 patients with SCA and 63 controls. The diagnosis of SCA was confirmed by DNA studies. Alpha thalassemia genotyping was performed by multiplex gap-PCR method. Laboratory parameters including complete blood count, hemoglobin quantitation, serum lactate dehydrogenase (LDH), and bilirubin were determined with standard techniques. RESULTS: Alpha thalassemia was found in 41 (41.0%) patients compared to 24 (38.1%) controls (P = 0.744), and all were due to the 3.7 κb α-globin gene deletions. Alpha thalassemia was associated with more frequent bone pain crisis, higher hemoglobin concentration, red blood cell count, and HbA2 level among the patients. On the contrary, patients with alpha thalassemia had lower mean corpuscular volume, mean corpuscular hemoglobin, and white blood cell count (WBC) (P Ë 0.05). There were 6 (6.0%) patients with leg ulcers, and none of them had alpha thalassemia, P = 0.04. CONCLUSION: This study confirms that coexistence of alpha thalassemia with SCA significantly influences both the clinical and laboratory manifestations of young Nigerian SCA patients. The coexistence of this genetic modifier is associated with increased bone pain crisis and protects against sickle leg ulcers among the patients.
Assuntos
Anemia Falciforme , Talassemia alfa , Adolescente , Adulto , Anemia Falciforme/sangue , Anemia Falciforme/epidemiologia , Anemia Falciforme/genética , Contagem de Células Sanguíneas , Criança , Pré-Escolar , Estudos Transversais , Feminino , Frequência do Gene , Hemoglobinas , Humanos , Masculino , Nigéria/epidemiologia , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Adulto Jovem , Talassemia alfa/sangue , Talassemia alfa/epidemiologia , Talassemia alfa/genéticaRESUMO
BACKGROUND: Increased destruction of erythrocytes in patients with sickle cell disease results in chronic hyperbilirubinemia and leads to the formation of gallstones. OBJECTIVES: The objective of this study was to determine the combined influence of alpha thalassemia, fetal hemoglobin, and the UGT1A1 polymorphism on serum bilirubin levels and cholelithiasis in patients with sickle cell disease. METHODS: We analyzed 72 patients treated in the outpatient hematology unit of the Clinical Hospital of Porto Alegre. The alpha thalassemia trait was determined by multiplex polymerase chain reaction and the polymorphisms of UGT1A1 by capillary electrophoresis with tagged primers. RESULTS: Total and indirect bilirubin levels differed significantly between genotypes TA7/TA7 and TA6/TA6 (p < 0.05). Bilirubin levels were influenced by the UGT1A1 polymorphism but not by alpha thalassemia and fetal hemoglobin. There was no association between cholelithiasis and any of the variables studied. CONCLUSION: These preliminary findings suggest that the UGT1A1 gene can influence serum bilirubin levels in sickle cell anemia and serve as a tool to differentiate an acute hemolytic condition from a pre-existing condition of hyperbilirubinemia.
Assuntos
Anemia Falciforme/diagnóstico , Bilirrubina/sangue , Colelitíase/diagnóstico , Hemoglobina Fetal/genética , Glucuronosiltransferase/genética , Polimorfismo Genético , Talassemia alfa/diagnóstico , Adolescente , Adulto , Anemia Falciforme/sangue , Anemia Falciforme/complicações , Anemia Falciforme/genética , Colelitíase/sangue , Colelitíase/complicações , Colelitíase/genética , Feminino , Hemoglobina Fetal/metabolismo , Expressão Gênica , Genótipo , Glucuronosiltransferase/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Talassemia alfa/sangue , Talassemia alfa/complicações , Talassemia alfa/genéticaRESUMO
α-Thalassemia (α-thal) is a hereditary hemoglobinopathy characterized by microcytic anemia due to impaired production of α chains of human globin. Brazilian studies show that the most common genotype is an -α(3.7) deletion with the loss of one or two α genes. As the production of α chains is not as accentuated in these cases, the correct diagnosis can only be achieved through molecular analysis that is not usually routinely performed by laboratories. We investigated the occurrence of α-thal babies born between September 2011 to January 2013 at the hospital of the Universidade Federal do Triângulo Mineiro (UFTM), Uberaba, Brazil, and blood donors of the Uberaba Regional Blood Center, Hemominas Foundation, Uberaba, Brazil, correlating it with ethnicity and differences between hematological parameters of donors, α-thal and iron deficiency patients. α-Thalassemia was investigated for the most common deleted alleles (-α(3.7), -α(4.2), - -(SEA), - -(FIL), - -(THAI), -(α)(20.5) and - -(MED)). The incidence in newborns was 13.16% with a predominance of heterozygosity for the -α(3.7) genotype (12.35%), followed by the -α(3.7)/-α(3.7) (0.46%) and αα/-α(4.2) genotypes (0.35%). In blood donors, the prevalence of α-thal was 14.89%, with all cases being heterozygous for the -α(3.7) deletion. There was an association of the α-thal genotype with African ancestors for both groups, thereby confirming published data and showing the strong influence of Blacks on the composition of the population of Brazil's southeastern region. Minor changes were found between hematological parameters of blood donors with iron deficiency and α-thal that did not contribute to the differential diagnosis between the two types of anemia.
Assuntos
Genótipo , alfa-Globinas/genética , Talassemia alfa/epidemiologia , Talassemia alfa/genética , Alelos , Anemia Ferropriva/sangue , Anemia Ferropriva/diagnóstico , Anemia Ferropriva/epidemiologia , Brasil/epidemiologia , Brasil/etnologia , Diagnóstico Diferencial , Índices de Eritrócitos , Frequência do Gene , Humanos , Incidência , Recém-Nascido , Talassemia alfa/sangue , Talassemia alfa/diagnósticoRESUMO
The α-thalassemia is one of the most common hereditary disorders worldwide. Currently, molecular diagnostics is the only available tool to achieve an accurate diagnosis. The purpose of this study was to characterize the molecular bases of these syndromes in our environment and to establish genotype-phenotype associations. Through a combination of different molecular techniques and fluorescent in situ hybridization (FISH),we were able to find α-thalassemic mutations in 145 of the 184 patients (78.8%) studied with hematological parameters compatible with α-thalassemia. Deletions of the α-globin genes resulted the major molecular cause of the disease, and the most frequent mutation was -α(3.7), found in homozygous and heterozygous genotypes. In patients with α° phenotypes, other prevalent mutations were( _MED) and (_CAL/CAMP). The description of a sub-telomeric deletion in a patient with α-thalassemia and mental retardation was also achieved. ß-thalassemic mutations in heterozygous state were found in 7.6% of the patients, who presented α-thalassemic clinical features (microcytosis and Hb A2levels below 3.5%). Hematologic profiles for the α+ and α° genotypes were established for adult and pediatric patients. Hopefully, this work will provide guidelines for the detection of possible α-thalassemic carriers. It also highlights the collaborative work of hematologists, the biochemical and molecular biology laboratory and genetists, in order to provide appropriate genetic counseling.
Assuntos
Genótipo , Hemoglobina A/genética , Deleção de Sequência , Talassemia alfa/genética , Adulto , Análise de Variância , Argentina/epidemiologia , Criança , Índices de Eritrócitos , Feminino , Estudos de Associação Genética , Heterozigoto , Homozigoto , Humanos , Hibridização In Situ , Masculino , Técnicas de Diagnóstico Molecular/métodos , Reação em Cadeia da Polimerase Multiplex , Mutação , Talassemia alfa/sangue , Talassemia alfa/epidemiologia , Talassemia alfa/patologiaRESUMO
La α-talasemia, es uno de los desórdenes hereditarios más frecuentes mundialmente. Al presente, el diagnóstico molecular es la única herramienta que permite el diagnóstico certero. El propósito de este trabajo fue caracterizar las bases moleculares de estos síndromes en nuestro medio, y establecer relaciones genotipo-fenotipo. Mediante la complementación de distintas técnicas de biología molecular e hibridación fluorescente in situ (FISH), se logró poner en evidencia la presencia de mutaciones α-talasémicas en 145 de 184 (78.8%) pacientes estudiados con perfil hematológico compatible con α-talasemia. Dentro de este grupo, las deleciones correspondieron al defecto genético más frecuente, prevaleciendo la mutación -α3.7 en genotipos heterocigotas y homocigotas. Asimismo, en pacientes con fenotipo α0 las deleciones prevalentes fueron -MED y -CAL/CAMP. Este estudio permitió también describir una deleción de la región sub-telomérica en un paciente con α-talasemia y retraso mental. En el 7.6% de los pacientes caracterizados clínicamente como posibles α-talasémicos (microcitosis con valores de Hb A2 inferiores al 3.5%), se hallaron mutaciones β-talasémicas en estado heterocigota. Se lograron establecer perfiles hematológicos asociados a los genotipos α+ y α0 para pacientes adultos y niños. Esperamos que este trabajo pueda servir como guía para reconocer posibles portadores α-talasémicos. También permite destacar el trabajo en conjunto de médicos hematólogos, el laboratorio (bioquímico y de biología molecular) y de los médicos genetistas, con el fin de proporcionar adecuado consejo genético.
The α-thalassemia is one of the most common hereditary disorders worldwide. Currently, molecular diagnostics is the only available tool to achieve an accurate diagnosis. The purpose of this study was to characterize the molecular bases of these syndromes in our environment and to establish genotype-phenotype associations. Through a combination of different molecular techniques and fluorescent in situ hybridization (FISH),we were able to find α-thalassemic mutations in 145 of the 184 patients (78.8%) studied with hematological parameters compatible with α-thalassemia. Deletions of the a-globin genes resulted the major molecular cause of the disease, and the most frequent mutation was -α3.7, found in homozygous and heterozygous genotypes. In patients with α0 phenotypes, other prevalent mutations were -MED and -CAL/CAMP. The description of a sub-telomeric deletion in a patient with α-thalassemia and mental retardation was also achieved. β-thalassemic mutations in heterozygous state were found in 7.6% of the patients, who presented α-thalassemic clinical features (microcytosis and Hb A2 levels below 3.5%). Hematologic profiles for the α+ and α0 genotypes were established for adult and pediatric patients. Hopefully, this work will provide guidelines for the detection of possible α-thalassemic carriers. It also highlights the collaborative work of hematologists, the biochemical and molecular biology laboratory and genetists, in order to provide appropriate genetic counseling.