Talassemia

Descrição Geral

Características da doença

• As talassemias são distúrbios hereditários da hemoglobina ( Hb Hb The oxygen-carrying proteins of erythrocytes. They are found in all vertebrates and some invertebrates. The number of globin subunits in the hemoglobin quaternary structure differs between species. Structures range from monomeric to a variety of multimeric arrangements. Gas Exchange) dos genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure α- ou β-globina. Defeitos nestes genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure levam a uma conformação anormal da hemoglobina levando a uma estrutura e função anormal dos eritrócitos.
• Apresenta-se como anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types microcítica hipocrómica:
  • Casos leves podem ser assintomáticos.
  • Casos graves podem levar a esplenomegalia, hemólise e anormalidades esqueléticas.

Epidemiologia

• Prevalência mundial:
  • α-talassemia: 5%; mais MAIS Androgen Insensitivity Syndrome comum na África e na Ásia
  • β-talassemia: 3%; mais MAIS Androgen Insensitivity Syndrome comum no Mediterrâneo
• Igual incidência em homens e mulheres

Etiologia

• Doença autossómica recessiva
• α-talassemia : 2 genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure α (HbA ₁ e HbA ₂) = 4 alelos (αα/αα)
  • Cromossoma 16: erro de deleção
  • 4 apresentações da doença:
    • Mínima: deleção do gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics 1 α
    • Minor: deleção de 2 genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure α (mesmo cromossoma = cis CIS Multiple Sclerosis, cromossomas opostos = trans)
    • Doença HbH HbH An abnormal hemoglobin composed of four beta chains. It is caused by the reduced synthesis of the alpha chain. This abnormality results in alpha-thalassemia. Thalassemia: deleção de 3 genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure α
    • Hb Barts Hb Barts Thalassemia: deleção de 4 genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure α
• β-talassemia: 1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics β (HbB) = 2 alelos
  • Cromossoma 11:
    • Mutação de splicing (β ⁺ : expressão diminuída) ou
    • Mutação nonsense (β ⁰ : expressão ausente)
  • 2 apresentações da doença:
    • Talassemia minor: heterozigótico, síntese diminuída de aproximadamente 50%
    • Talassemia major: homozigótico, sem produção de β globulina, aumento de HbA₂(α₂δ₂) e HbF (α₂γ₂), sem HbA

Fisiopatologia

• Formação anormal da Hb Hb The oxygen-carrying proteins of erythrocytes. They are found in all vertebrates and some invertebrates. The number of globin subunits in the hemoglobin quaternary structure differs between species. Structures range from monomeric to a variety of multimeric arrangements. Gas Exchange: leva à agregação da Hb Hb The oxygen-carrying proteins of erythrocytes. They are found in all vertebrates and some invertebrates. The number of globin subunits in the hemoglobin quaternary structure differs between species. Structures range from monomeric to a variety of multimeric arrangements. Gas Exchange que danifica as membranas dos glóbulos vermelhos (GV).
• Os GV danificados sofrem hemólise, resultando em:
  • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
  • Cálculos biliares pigmentados
• A eritropoiese ineficaz (devido à falta de componentes normais de Hb Hb The oxygen-carrying proteins of erythrocytes. They are found in all vertebrates and some invertebrates. The number of globin subunits in the hemoglobin quaternary structure differs between species. Structures range from monomeric to a variety of multimeric arrangements. Gas Exchange) leva a:
  • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types → insuficiência cardíaca de alto débito
  • Expansão da medula óssea
  • Hematopoiese extramedular → hepatomegalia e/ou esplenomegalia
• Sobrecarga de ferro (pelas múltiplas transfusões para compensar os GV nativos danificados)
  • Aumento compensatório na captação GI de ferro
  • Endocrinopatias

Apresentação Clínica

Diagnóstico

Estudos iniciais

• História médica e familiar completa (++ em áreas de alto risco).
• Solicitar hemograma completo com índices eritrocitários e esfregaço de sangue periférico.
• No hemograma:
  • Hb Hb The oxygen-carrying proteins of erythrocytes. They are found in all vertebrates and some invertebrates. The number of globin subunits in the hemoglobin quaternary structure differs between species. Structures range from monomeric to a variety of multimeric arrangements. Gas Exchange → geralmente < 11 g/dL ou < 6 g/dL na anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types de Cooley
  • VCM → microcítico (< 70 fL) nas talassemias
  • HCM HCM Hypertrophic cardiomyopathy (HCM) is the most commonly inherited cardiomyopathy, which is characterized by an asymmetric increase in thickness (hypertrophy) of the left ventricular wall, diastolic dysfunction, and often left ventricular outflow tract obstruction. Hypertrophic Cardiomyopathy → baixa em talassemias
  • Distribuição dos eritrócitos → pouco útil nas talassemias (pode ser normal ou elevada)
• No esfregaço de sangue periférico:
  • Células-alvo ( mais MAIS Androgen Insensitivity Syndrome comuns)
  • Corpo de Howell-Jolly: pontinhado azul nos GV (remanescentes de DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure)
  • Anisocitose: hemácias de tamanhos diferentes
  • Corpos de inclusão: vistos apenas na doença da hemoglobina H ( HbH HbH An abnormal hemoglobin composed of four beta chains. It is caused by the reduced synthesis of the alpha chain. This abnormality results in alpha-thalassemia. Thalassemia) (agregação 4 β)
  • Corpos de Heinz: mancha vermelha na periferia das hemácias ( Hb Hb The oxygen-carrying proteins of erythrocytes. They are found in all vertebrates and some invertebrates. The number of globin subunits in the hemoglobin quaternary structure differs between species. Structures range from monomeric to a variety of multimeric arrangements. Gas Exchange desnaturada)
  • Pontilhado basófilo
  • Para lembrar as características vistas num esfregaço de sangue periférico de um paciente com talassemia, temos a mnemónica THAL:
    • Target cell – Células em alvo ( mais MAIS Androgen Insensitivity Syndrome comum)
    • Howell – Jolly body – Corpos de Howell – Jolly
    • Anisocytosis – anisocitose
    • Low MCH, MCV and Hb Hb The oxygen-carrying proteins of erythrocytes. They are found in all vertebrates and some invertebrates. The number of globin subunits in the hemoglobin quaternary structure differs between species. Structures range from monomeric to a variety of multimeric arrangements. Gas Exchange – VCM, HCM HCM Hypertrophic cardiomyopathy (HCM) is the most commonly inherited cardiomyopathy, which is characterized by an asymmetric increase in thickness (hypertrophy) of the left ventricular wall, diastolic dysfunction, and often left ventricular outflow tract obstruction. Hypertrophic Cardiomyopathy e Hb Hb The oxygen-carrying proteins of erythrocytes. They are found in all vertebrates and some invertebrates. The number of globin subunits in the hemoglobin quaternary structure differs between species. Structures range from monomeric to a variety of multimeric arrangements. Gas Exchange diminuídos
• Se houver suspeita de hemólise, solicitar LDH LDH Osteosarcoma:
  • Se a LDH LDH Osteosarcoma estiver elevada e houver suspeita de hemólise, pedir a contagem de reticulócitos: elevada na doença de HbH HbH An abnormal hemoglobin composed of four beta chains. It is caused by the reduced synthesis of the alpha chain. This abnormality results in alpha-thalassemia. Thalassemia.
• Estudo da cinética do ferro: normal nas talassemias, anormal em outras causas de anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types

Estudos confirmatórios

• Se os estudos de ferro forem normais, pedir eletroforese de Hb Hb The oxygen-carrying proteins of erythrocytes. They are found in all vertebrates and some invertebrates. The number of globin subunits in the hemoglobin quaternary structure differs between species. Structures range from monomeric to a variety of multimeric arrangements. Gas Exchange.
• Os estudos normais de eletroforese de Hb Hb The oxygen-carrying proteins of erythrocytes. They are found in all vertebrates and some invertebrates. The number of globin subunits in the hemoglobin quaternary structure differs between species. Structures range from monomeric to a variety of multimeric arrangements. Gas Exchange mostram:
  • HbA: 95%
  • HbA₂: 3%–5%
  • HbF: quantidade mínima
  • Sem HbH HbH An abnormal hemoglobin composed of four beta chains. It is caused by the reduced synthesis of the alpha chain. This abnormality results in alpha-thalassemia. Thalassemia ou Hb Barts Hb Barts Thalassemia com eletroforese de Hb Hb The oxygen-carrying proteins of erythrocytes. They are found in all vertebrates and some invertebrates. The number of globin subunits in the hemoglobin quaternary structure differs between species. Structures range from monomeric to a variety of multimeric arrangements. Gas Exchange normal
• Na α-talassemia:
  • Mínima: percentagem normal de HbA e HbA ₂
  • Minor (traço talassémico): percentagem normal de HbA e HbA₂, mas o hemograma mostra anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
  • Doença de HbH HbH An abnormal hemoglobin composed of four beta chains. It is caused by the reduced synthesis of the alpha chain. This abnormality results in alpha-thalassemia. Thalassemia: β-tetrâmeros (ou seja, a eletroforese de Hb Hb The oxygen-carrying proteins of erythrocytes. They are found in all vertebrates and some invertebrates. The number of globin subunits in the hemoglobin quaternary structure differs between species. Structures range from monomeric to a variety of multimeric arrangements. Gas Exchange mostrará apenas uma banda β)
  • Hb Barts Hb Barts Thalassemia: γ-tetrâmeros (ou seja, a eletroforese de Hb Hb The oxygen-carrying proteins of erythrocytes. They are found in all vertebrates and some invertebrates. The number of globin subunits in the hemoglobin quaternary structure differs between species. Structures range from monomeric to a variety of multimeric arrangements. Gas Exchange mostrará apenas uma banda γ)
• Na β-talassemia
  • Minor:
    • ↓ HbA (93%)
    • ↑ HbA₂ (5%)
    • ↑ HbF (2%)
  • Maior:
    • Sem HbA
    • ↑ HbF (90%)
    • ↑ HbA₂ (10%)
• Outros estudos auxiliares:
  • A radiografia mostrará osteopenia Osteopenia Osteoporosis e crânio com aparência de “cabelos em pé”.
  • Um ecocardiograma pode mostrar uma redução na fração de ejeção do ventrículo esquerdo.

Tratamento

α- e β-talassemia minor

• Os pacientes geralmente são assintomáticos e nenhuma terapia crónica está indicada.
• A suplementação periódica de folato pode ser útil durante períodos de stresse fisiológico (p. ex., gravidez).
• Aconselhamento genético em relação ao risco na descendência.

Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types de Cooley e doença HbH HbH An abnormal hemoglobin composed of four beta chains. It is caused by the reduced synthesis of the alpha chain. This abnormality results in alpha-thalassemia. Thalassemia

• Transfusões:
  • Os pacientes são dependentes de transfusão.
  • Nível alvo de Hb Hb The oxygen-carrying proteins of erythrocytes. They are found in all vertebrates and some invertebrates. The number of globin subunits in the hemoglobin quaternary structure differs between species. Structures range from monomeric to a variety of multimeric arrangements. Gas Exchange > 10 g/dL
  • Suplementação de folato, se não transfundido
• Esplenectomia e colecistectomia:
  • As esplenectomias reduzem as necessidades de transfusão.
  • Vacinas pós-esplenectomia (organismos encapsulados)
    • Anti-pneumocócica
    • Haemophilus influenzae Haemophilus Influenzae A species of Haemophilus found on the mucous membranes of humans and a variety of animals. The species is further divided into biotypes I through viii. Haemophilus tipo b
    • Conjugado pneumocócico
  • Colecistectomia para prevenir cálculos biliares recorrentes
• Quelantes de ferro:
  • Reduz os níveis séricos de ferro
  • Desferoxamina (IV)
  • Deferiprona/ deferasirox Deferasirox A triazole and benzoate derivative that acts as a selective iron chelator. It is used in the management of chronic iron overload due to blood transfusion or non-transfusion dependent thalassemia. Hereditary Hemochromatosis (formulações orais)
• Terapia endócrina:
  • Administrar hormonas em falta.
  • Bisfosfonatos para prevenir osteopenia Osteopenia Osteoporosis e osteoporose
  • Agentes de fertilidade
• Terapia definitiva: transplante alogénico de células-estaminais
• Aconselhamento genético

Diagnóstico Diferencial

O diagnóstico diferencial inclui outras doenças associadas à anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types microcítica ou com células em alvo.

• Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types por deficiência de ferro: causa principal de anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types microcítica hipocrómica além da talassemia. Os pacientes podem apresentar palidez e fadiga fácil. Estudos de ferro são necessários para obter o diagnóstico. Os resultados do estudo de ferro indicarão níveis reduzidos de ferro e um aumento da capacidade total de ligação do ferro. O tratamento é feito com suplementação oral de ferro.
• Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types das doenças crónicas (“ anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types de inflamação crónica”): secundária a doença inflamatória, infeciosa ou maligna. Os pacientes apresentam achados semelhantes aos da deficiência de ferro, como a palidez e a fadiga fácil. Estudos de ferro revelarão baixos níveis de ferro sérico e transferrina; entretanto, os níveis de ferritina estarão normais ou aumentados. O tratamento é direcionado para a resolução da doença crónica subjacente.
• Doença hepática: As células em alvo podem ser vistas no esfregaço de sangue periférico de pacientes com doença hepática. Essas células em alvo, de aparência grande e de um alvo, são formadas devido ao excesso de lipídios na membrana.
• Pacientes pós-esplenectomia: Células em alvo e corpos de Howell-Jolly aparecem no esfregaço de sangue periférico de pacientes após esplenectomia. Os pacientes também podem ter um aumento leve a acentuado na contagem de plaquetas (trombocitose).