Thalassemia

Thalassemiasv are categorized by reduced or no production of hemoglobin and chronic anemia of varying severity.

Beta thalassemia is relatively rare in the United States, but is one of the most common autosomal recessive disorders in the world.

Thalassemias refer to diseases of hemoglobin synthesis, with subtypes named by the hemoglobin type involved.

Thalassemia is subdivided into Alpha thalassemia and data thalassemia, depending upon the underlying genetic mutation and affected globin-gene subunits within the hemoglobin tetramer.

Individuals with beta thalassemia minor have a mutation in one HBB gene, while individuals with the intermediate and major forms have mutations in both HBB genes.

Many individuals with beta thalassemia minor go through life never knowing they carry an altered gene for the disorder.

Individuals with beta thalassemia minor usually do not develop symptoms and do not require treatment.

It is important that individuals with beta thalassemia minor be correctly diagnosed, however, in order to avoid unnecessary treatments for similarly-appearing conditions such as iron deficiency anemia.

Individuals with beta thalassemia intermedia occasionally require blood transfusions such as when suffering from an illness or infection or when planning to undergo surgery.

Beta thalassemia is an inherited blood disorder characterized by reduced levels of functional hemoglobin.

Most beta thalassemia cases are caused by a mutation in the HBB gene.

In extremely rare cases, a loss of genetic material that includes the HBB gene causes the disorder.

Genes provide instructions for creating proteins that play a critical role in many body functions.

The characteristic finding of beta thalassemia is anemia, which is caused because red blood cells are abnormally small, are not produced at the normal amounts, and do not contain enough functional hemoglobin.

Hemoglobin is found in red blood cells; it is the red, iron-rich, oxygen-carrying pigment of the blood.

Affected individuals do not receive enough oxygen-rich blood throughout the body.

Affected individuals may experience classic signs of anemia including fatigue, weakness, shortness of breath, dizziness or headaches.

Severe anemia can cause serious, even life-threatening complications if left untreated.

A main function of red blood cells is to deliver oxygen throughout the body.

Each chromosome 16 carries two copies of gene encoding the alpha genes.

There are 4 types of alpha-thalassemia: trait 1, trait 2, hemoglobin H disease and hemoglobin Bart’s.

Alpha thalassemia associated with chronic low-grade hemolysis.

Alpha thalassemia trait has a prevalence that approaches 30% in African-Americans.

The severity of alpha thalasemia and beta thalassemia depends upon the number of genes absent to produce alpha globin (four genes), or the type of mutation affecting beta globin (two genes).

The presence of HbH, known as alpha thalassemia hemoglobin H disease.

Hemoglobin Bart’s lacks alpha-chain production, which results hydrops fetalis do the lack of fetal and adult hemoglobin production.

Deletion of or mutations in three alpha-chain genes lead to hemoglobin H disease.

Hemoglobin H ranges from a mild to severe chronic hemolytic anemia.

Beta thalassemia may also occur along with another disorder in which there is an abnormality in the structure of hemoglobin.

This includes hemoglobin E (HbE/beta thalassemia), hemoglobin C (HbC/beta thalassemia), and hemoglobin S (HbS/beta thalassemia); a condition that resembles sickle cell anemia and is sometimes referred to as sickle beta thalassemia.

Beta thalassemia has three main forms – minor, intermedia and major, which indicate the severity of the disease.

Individuals with beta thalassemia minor usually do not have any symptoms and individuals often are unaware that they have the condition.

Some individuals do experience a very mild anemia.

Beta thalassemia intermedia’s are widely variable and severity falls in the broad range between the two extremes of the major and minor forms.

When the disorder develops later during life, a diagnosis of beta thalassemia intermedia is given; individuals may only require blood transfusions on rare, specific instances.

Individuals with beta thalassemia major have a severe expression of the disorder; they often require regular blood transfusions and lifelong, ongoing medical care.

With beta thalassemia major, initial symptoms often become apparent during the first two years of life and include failure to thrive, a swollen abdomen, and symptoms of anemia.

Beta thalassemia intermedia may be suspected in individuals who present with similar, yet milder, symptoms, but at a later age.

The classic clinical picture of beta thalassemia major is primarily seen in countries with insufficient resources to provide affected individuals with appropriate treatment of regular transfusions and iron-lowering medications.

Iron overload results from the blood transfusions required to treat individuals with beta thalassemia major.

Affected individuals experience greater iron absorption from the gastrointestinal tract, which contributes to iron overload.

Iron overload can cause tissue damage and impaired function of affected organs such as the heart, liver and endocrine glands.

Iron overload can damage the heart causing abnormal heart rhythms, inflammation of the pericardium, enlargement of the heart.

Heart involvement can progress to life-threatening complications such as heart failure.

Liver involvement can cause cirrhosis) and portal hypertension.

Endocrine gland involvement can cause insufficiency of certain glands such as the thyroid (hypothyroidism) and, in rare cases, diabetes mellitus.

Iron overload can also be associated with growth retardation and the failure or delay of sexual maturation.

Individuals with beta thalassemia major and intermedia may develop iron overload, which occurs because of two reasons: First, blood transfusions cause the accumulation of excess iron in the body.

Second, beta thalassemia can cause increased absorption of dietary iron by the gastrointestinal tract.

The body has no normal way to remove excess iron.

In individuals who receive regular blood transfusions, iron overload primarily occurs because of treatment.

Iron overload is treated by medications that remove excess iron from the body such as deferoxamine, deferiprone and deferasirox, which are iron chelators.

Individuals with trait thalassemias have no or very mild anemia and variable microcytosis.

Patients with thalassemia trait 2 have more pronounced anemia and microcytosis then other forms.

Beta-thalasemia abnormal genes carried by close to 3% of the world’s population.

The most common monogenic disorder in the world.

Abnormalities in structure and synthesis of alpha like and β-like globin chains that form tertamers of hemoglobin lead to the most common forms of inheritied anemias.

Estimated that worldwide there are 270 million carriers of mutant globin alleles which can potentially cause severe forms of thalassemia and hemoglobinopathy.

Approximately 1-2000 patients with severe thalassemia in the US.

Every year 300-400,000 severely affected children are born, and 95% of these births occur in Asia, India, and the Middle East.

Incidence highest Mediterranean, Greek, Italian, Middle Eastern, Indian, East/Southeast Asia, and Africa: As thalassemia carriers have resistance to malaria the geographic distribution of the 2 disorders overlap.

The evolutionary association between the thalassemia carrier state and resistance to malaria explains its high prevalence in the above areas.

Population migrations introduce thalassemia to Europe and the Americas.

Severely affected children have pallor, irritability, poor feeding and weight gain, and hepatosplenomegaly.

Detected by hemoglobin electrophoresis or chromic photography.

Definitive genetic testing with L is elevation of DNA is another option.

Polychromasia, basophilic stippling and target cells seen on peripheral smear.

Alpha-thalassemia occurs when there is a deficiency in alpha globulin expression.

The major geographic location for alpha-thalassemia includes Africa, the Mediterranean area, snd South East Asia.

Hemoglobin H disease and hemoglobin Bart’s disease are seen only in the Mediterranean area and Southeast Asia.

In alpha-thalassemia, alpha-globin gene mutations inhibit production of the corresponding protein.

In alpha-thalassemia the lesions that remove one or more entire genes are present.

In-alpha-thalassemia there is an accumulation of excess beta-globulin, which forms a homotetramer Beta4, hemoglobin H.

In neonates with alpha-thalassemia, accumulation of fetal globulin tetramer gamma4. hemoglobin Barts can be detected by routine newborn screening.

In alpha-thalassemia most cases are caused by deletion of 1 or more of the 4 alpha-globin genes normally present.

In alpha-thalassemia the severity disease correlates with a number of alpha-globin genes lost.

In alpha-thalassemia deletions of 1 or 2 alpha-globulin genes resulting a silent carrier state, alpha-thalassemia trait, and usually cause no symptoms.

Two molecular forms of alpha-thalassemia trait 2 exist-one in which one copy of the gene is mutated on each chromosome referred to as trans, and the other in which one chromosome has both genes mutated referred to as sis.

The predominant genotype of thalassemia trait in Africa is trans, and the cod form is found in ther areas and can lead to hemoglobin H and hemoglobin Bart”s.

In alpha-thalassemia the loss of 3 genes causes mild to severe anemia exacerbated by fever and/or infections.

In alpha-thalassemia deletions of all 4 alpha-globin genes may cause death, fetal hydrops, and occurs most frequently and some parts of Asia.

Beta-thalassemia occurs when Beta-globulin synthesis is downgraded.

In beta-thalassemia there are beta-globin gene mutations that inhibit the production of the corresponding protein.

In beta-thalassemia free alfa-globin accumulates which is toxic to blood cells and their precursors.

Individuals diagnosed with beta thalassemia intermedia have a widely varied expression of the disorder.

Moderately severe anemia is common and affected individuals may require periodic blood transfusions.

Common symptoms include pallor, jaundice, leg ulcers, gallstones, and abnormal enlargement of the liver and spleen.

Moderate to severe skeletal malformations may also occur.

Normally, here to beta-globin genes and loss of 1 gene usually causes beta thalassemia trait.

Beta thalassemia trait is usually asymptomatic although red blood cells are small.

Both beta-globin genes must be mutated because symptomatic beta-thalassemia.

Beta-thalassemia medications include gene deletions and more commonly point mutations inhibiting transcription, splicing, and translation of genes.

Beta thalassemia is more heterogeneous than alpha-thalassemia with a spectrum of clinical disease depending on the mutations and reduction of beta-globin gene expression.

Beta thalassemia has different forms and include beta thalassemia trait, Beta thalassemia minor,

Beta-thalassemia intermedia and Beta thalassemia major: the disorder is a continuous clinical spectrum with an increasing order of severity.

Carriers of alpha-thalassemia and Beta-thalassemia are clinically normal but may have hypochromic microcytic anemia.

Because of repeated blood transfusions individuals with beta thalassemia major and intermedia they may develop excess levels of iron in the body.

Iron overload can cause a variety of symptoms affecting multiple systems of the body, but can be treated with medications.

Splenomegaly may cause abdominal enlargement or swelling.

Splenomegaly may be associated with hypersplenism, a condition that can develops because too many blood cells build up and are destroyed within the spleen.

Hypersplenism can contribute to anemia in individuals with beta thalassemia and cause low levels of white blood cells, increasing the risk of infection, and low levels of platelets, which can lead to prolonged bleeding.

Some individuals may be treated by the surgical removal of the spleen.

Splenomegaly can cause severe pain and contribute to anemia.

Splenomegaly can cause thrombocytopenia.

An enlarged spleen in individuals with beta thalassemia may occur due to increased destruction of red blood cells, extramedullary hematopoiesis, repeated blood transfusions, or iron overload.

If other forms of therapy fail, removal of the spleen may be considered.

If a splenectomy is required, one month before the surgery pneumococcal conjugate vaccine should be given.

In addition, antibiotic prophylaxis, usually penicillin 250 mg twice a day, is given the first two years after surgery and for children younger than 16 years.

Because of advances in the treatment of beta thalassemia in the past several years, splenectomy is rarely necessary as a treatment for affected individuals.

Elevated liver iron predicts for poor endocrine and cardiovascular outcomes in thalassemia major.

In thalassemia major patients who do not receive treatment with iron chelation have a mean survival of 12-17 years, with death mainly from cardiac failure or arrhythmia.

Cardiac disease is the main life-threatening complication in individuals with beta thalassemia.

In thalassemia major, iron overload due to blood transfusions is aggravated by inappropriately increased absorption of dietary iron.

GDF highly expressed in beta-thalassemia and suppresses transcription of hepcidin.

Is homozygous beta thalassemia the rate of iron absorption is elevated and iron overload develops over time, usually due to blood transfusions, but iron overload can occur independently of blood transfusions because hepcidin is suppressed, by ineffective hematopoiesis.

Decreased hepcidin leads to increased intestinal iron absorption and it is released from macrophages in the reticuloendothelial system.

Thalassemia clinical problems: anemia and ineffective erythropoiesis.

Ineffective erythropoiesis causes bone deformities and fractures, and extra medullary hematopoiesis.

Extramedullary hematopoietic masses primarily form in the spleen, liver, lymph nodes, chest, and spine and can potentially cause compression of nearby structures and a variety of symptoms.

When facial bones are affected it can result in distinctive facial features including an abnormally prominent forehead, full cheek bones, a depressed bridge of the nose, and overgrowth of the upper jaw, exposing the upper teeth.

The affected bones have an increased fracture risk, particularly the long bones of the arms and legs.

Some individuals may develop knock knees a condition in which the legs bend inward so that when a person is standing the knees will touch even if the ankles and feet are not.

Patients that are missing all four alpha-globin genes die before birth unless they receive in utero blood transfusions: and then transfusions are required throughout life.

Patients with three affected alpha-globin genes have an intermediate form of thalassemia.

Newborns with beta- thalassemia are well in the newborn period, and become symptomatic during the first year of life when hemoglobin F synthesis declines.

Thalassemia major, an inherited failure to synthesize the beta-globulin chain of hemoglobin, is the most common disease resulting in transfusion dependency worldwide.

Patients with thalassemia major will require transfusions every 3-4 weeks to function normally.

The mean survival of patients who do not receive treatment with iron chelation is 12-17 years, with death occurring mainly from cardiac failure or arrhythmia.

Affected infants exhibit symptoms within the first two years of life, often between 3 and 6 months after birth.

The classic description of beta thalassemia major tends to primarily occur in developing countries.

Allthough beta thalassemia major is a chronic, lifelong illness, if individuals follow the current recommended treatments, most individuals can live happy, fulfilling lives.

Patients with thalassemia major develop iron excess disease as teenagers and young adults and die frequently of iron overload.

Affected infants often fail to grow and gain weight as expected based upon age and gender, have feeding problems, diarrhea, irritability or fussiness, recurrent fevers, abnormal enlargement of the liver, and the abnormal enlargement of the spleen may also occur.

The treatment initially for iron overload is deferoxamine ( Desferal) given subcutaneously or intravenously for 8 to 12 hours nightly to be effective.

Additional oral chelating agents available include deferasirox (Exjade) and Deferiprone (Ferriprox).

MRI allows imaging and quantification of tissue iron so that chelation therapy based on organ specific iron loading can be achieved.

Repeated measurements showing serum ferritin levels above 2500 ng/mL are associated with increased risk of heart disease and death, whereas levels below 1000 mg per millimeter are associated with prolonged survival.

 Liver iron concentrations above 7 mg program or associated with increased risk of Liver disease, and concentrations above 15 mg program are associated with an increased risk of heart disease.

T2 weighted measurements of myocardial iron of less than 20 ms are associated with cardiac arrhythmias and less than 10 ms are associated with heart failure or death.

Extramedullary hematopoiesis common.

Abnormal expansion of the bone marrow causes bones to become thinner, wider and brittle.

Affected bones may grow abnormally, particularly the long bones of the arms and legs and certain bones of the face.

Pulmonary hypertension common in severe thalassemia.

Thought excess free hemoglobin causes endothelial injury as well as nitric oxide depletion leading to pulmonary hypertension.

Splenectomy and older age are risk factors for pulmonary hypertension.

Bone marrow transplantation is an effective treatment for severe forms of thalassemia with cure rates approaching 90% in appropriately selected patients.

Individuals with beta thalassemia are treated with allogeneic stem cell transplantation.

Ideally, a hematopoietic stem cell transplant should be done before the age of 16 and before the onset of hepatomegaly, portal fibrosis, or iron overload.

Non–transfusion dependent patients include patients with three alpha-globin genes deleted, beta-thalassemia intermedia or E hemoglobin beta-thalassemia.

Patients with thalassemia minor or thalassemia trait require no therapy.