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Thalassemia

Thalassemic Syndrome

Thalassemia is a genetic disorder, most commonly encountered in countries with malaria prevalence or in people of corresponding descent. In affected individuals, hemoglobin synthesis is disturbed, which leads to hypochromic microcytic anemia of different severity.

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Presentation

Clinical presentation of thalassemia varies widely. And while some mutations are known to be particularly severe, the large number of different mutations and combinations thereof doesn't allow for the deduction of which genes are affected from physical examination or evaluation of blood counts. Thus, clinically, minor, intermediate and major forms of the disease are distinguished with regards to the severity:

  • Most carriers have minor thalassemia and this condition is largely asymptomatic. Patients don't generally report any complaints, but their hemogram may reveal mild hypochromic microcytic anemia. This is refractory to iron substitution and this observation is often the basis of a thalassemia-oriented workup.
  • Thalassemia intermedia is additionally associated with severe hemolytic and aplastic crises. During such episodes, which may be induced by infection, folate deficiency or pregnancy [9], transfusions of blood products may become necessary.
  • Major thalassemia is a debilitating, life-threatening disease and affected people require life-long support and regular transfusions.

In symptomatic thalassemia, symptoms provoked by anemia and hemolysis dominate the clinical picture. Patients may claim frequent headaches, dizziness, exertional dyspnea and palpitations. The reduced capacity for oxygen transport causes pallor and fatigue, and hemolysis results in jaundice and splenomegaly. Skeletal deformations may be observed and are due to bone marrow overstimulation and consequent expansion of erythroid cells.

Splenomegaly
  • KEYWORDS: Anemia; genotype-phenotype; hemolysis; relationship; splenomegaly; β-thalassemia intermedia (β-TI)[ncbi.nlm.nih.gov]
  • Enlarged spleen (splenomegaly). The spleen helps your body fight infection and filter unwanted material, such as old or damaged blood cells.[web.archive.org]
  • Clinical description Patients present with moderate to severe anemia, jaundice and splenomegaly.[orpha.net]
  • The infant developed anemia, splenomegaly, and began transfusion therapy by the age 6 of months. This is the first report of β-thalassemia major with homozygous IVS-II-849 (A G) mutations.[ncbi.nlm.nih.gov]
  • No splenomegaly was present. FAMILY HISTORY: Both parents carry sickle cell thalassemia. PRINCIPAL LABORATORY FINDINGS: Table 1, Table 2, and Image 1. Copyright by the American Society for Clinical Pathology (ASCP).[ncbi.nlm.nih.gov]
Anemia
  • Thalassemia major (Cooley anemia) is characterized by severe anemia, enlargement of the spleen, and body deformities associated with expansion of the bone marrow.[britannica.com]
  • Anemia prevalence was higher in children and women with homozygous sickle cell (HbSS).[ncbi.nlm.nih.gov]
  • Mild anemia caused by alpha thalassemia trait might be mistaken for iron-deficiency anemia. Mild to Moderate Anemia and Other Signs and Symptoms People who have beta thalassemia intermedia have mild to moderate anemia.[web.archive.org]
  • Anemia results from this abnormal hemoglobin formation An inherited form of anemia Heterogeneous group of hereditary hemolytic anemias which have in common a decreased rate of synthesis of one or more hemoglobin polypeptide chains If you have thalassemia[icd9data.com]
  • It causes mild anemia. If both genes are altered, you'll have beta thalassemia intermedia or beta thalassemia major (also called Cooley's anemia). The intermedia form of the disorder causes moderate anemia. The major form causes severe anemia.[web.archive.org]
Weakness
  • Abstract We report a case of a thalassemia major male patient with back pain associated to severe weakness in lower extremities resulting in the ability to ambulate only with assistance.[ncbi.nlm.nih.gov]
  • This is a condition in which bones are weak and brittle and break easily.[web.archive.org]
  • For example, you may feel weak, tire out more easily, and feel short of breath. Other symptoms also can occur depending on how severe your disease is and what problems it causes.[northshore.org]
  • This abnormal hemoglobin is reduced in its capacity to transport oxygen around the body, which leads to anemia, fatigue, weakness and shortness of breath.[news-medical.net]
Pallor
  • Clinical description Onset is during infancy with severe anemia, failure to thrive and progressive pallor.[orpha.net]
  • Common symptoms include pallor, jaundice, leg ulcers, gallstones (cholelithiasis), and abnormal enlargement of the liver and spleen. Moderate to severe skeletal malformations (as described in beta thalassemia major) may also occur.[rarediseases.org]
  • These conditions provoke pallor or jaundice, fatigue, headaches and dizziness. Patients may have breathing difficulties under exercise.[symptoma.com]
  • Other symptoms include: poor growth pallor jaundice enlargement of the liver and spleen due to the breakdown of red cells containing the abnormal hemoglobin leg ulcers bone changes secondary to marrow expansion the appearance of other masses due to the[news-medical.net]
  • Because the anemia is never severe and, in most instances, the Hb level is not less than 9-10 g/dL, pallor and splenomegaly are rarely observed.[emedicine.medscape.com]
Short Stature
  • For instance, patients may be of short stature or have bone deformities or impaired fertility—all of which could affect how they think of themselves and how they think others see them.[celgene.com]
  • Endocrine dysfunction secondary to iron overload is common in multiply transfused patients, manifesting as hypogonadotrophic hypogonadism, short stature, acquired hypothyroidism, hypoparathyroidism and diabetes mellitus. [ 13 ] Glycated haemoglobin (HbA1c[patient.info]
Family History of Anemia
  • Antenatal screening should be considered in these ethnic groups who have immigrated, especially in those with a family history of anemia.[clinicaladvisor.com]
Dyspnea
  • He presented with chest discomfort and progressive dyspnea. Early echocardiogram showed mild pericardial effusion. Four days later, the effusion had increased, impending to cardiac temponade requiring pericardectomy.[ncbi.nlm.nih.gov]
  • Patients may claim frequent headaches, dizziness, exertional dyspnea and palpitations. The reduced capacity for oxygen transport causes pallor and fatigue, and hemolysis results in jaundice and splenomegaly.[symptoma.com]
  • Non-transfusion dependent thalassemia The most common symptoms of non-transfusion dependent thalassemia are related to anemia: pale skin, lips, hands or under the eyelids increased heart rate (tachycardia) breathlessness, or difficulty catching a breath (dyspnea[danafarberbostonchildrens.org]
Exertional Dyspnea
  • Patients may claim frequent headaches, dizziness, exertional dyspnea and palpitations. The reduced capacity for oxygen transport causes pallor and fatigue, and hemolysis results in jaundice and splenomegaly.[symptoma.com]
Malocclusion
  • CASE DESCRIPTION: A 16-year-old female patient with β-thalasse-mia major was referred with the complaints of severe facial deformity and malocclusion, resulting in psychosocial and functional problems for her.[ncbi.nlm.nih.gov]
  • […] diploic space thinning of the inner and outer table facial bones rodent facies hypopneumatisation of the frontal, maxillary, and sphenoid sinuses, filled with marrow containing bone 6 the ethmoid sinuses are spared due to lack of red bone marrow 6 dental malocclusion[radiopaedia.org]
  • Thalassemia can result in maxillary enlargement, leading to an appearance known as chipmunk face, along with increased spaces between teeth, overbite, and malocclusion.[emedicine.medscape.com]
  • Bony abnormalities, such as frontal bossing, prominent facial bones, and dental malocclusion, are usually striking. Severe pallor, slight to moderately severe jaundice, and marked hepatosplenomegaly are almost always present.[emedicine.medscape.com]
  • Bony deformities (frontal bossing, prominent facial bones, and dental malocclusion). Marked pallor and slight to moderate jaundice. Exercise intolerance, cardiac flow murmur or heart failure secondary to severe anaemia.[patient.info]
Heart Failure
  • KEYWORDS: Cardiomyopathy; T2* cardiac magnetic resonance (T2* CMR); diastolic dysfunction; heart failure (HF); iron overload; β-Thalassemia major (β-TM)[ncbi.nlm.nih.gov]
  • Severe thalassemia can cause early death (between ages 20 and 30) due to heart failure. Getting regular blood transfusions and therapy to remove iron from the body helps improve the outcome.[nlm.nih.gov]
  • Increased parathyroid hormone (PTH) is also known to be associated with heart failure.[ncbi.nlm.nih.gov]
  • Heart problems, such as congestive heart failure and abnormal heart rhythms (arrhythmias), may be associated with severe thalassemia. References What are thalassemias? National Heart, Lung, and Blood Institute. . Accessed Dec. 30, 2010.[web.archive.org]
  • Infants who survive to be born have massive total body edema with high-output congestive heart failure due to the severe anemia. They also have massive hepatomegaly due to heart failure and extramedullary hematopoiesis.[emedicine.medscape.com]
Palpitations
  • Patients may claim frequent headaches, dizziness, exertional dyspnea and palpitations. The reduced capacity for oxygen transport causes pallor and fatigue, and hemolysis results in jaundice and splenomegaly.[symptoma.com]
  • […] contain iron, aluminum, or zinc. 2 Risk of nausea, which may be decreased by taking deferiprone with food. 1 Possibility of reddish/brown discoloration of the urine, which is not harmful. 1 Importance of seeking immediate medical attention in case of palpitations[web.archive.org]
  • Stage III patients have symptoms ranging from palpitations to congestive heart failure. The ejection fraction on echocardiography is decreased. There is normal or decreased ejection fraction on cineangiogram at rest, and it falls on exercise.[patient.info]
Jaundice
  • Clinical description Patients present with moderate to severe anemia, jaundice and splenomegaly.[orpha.net]
  • Diagnostic methods Diagnosis is suspected in infants younger than 2 years of age with severe microcytic anemia, mild jaundice and hepatosplenomegaly.[orpha.net]
  • Affected individuals may develop mild to moderate anemia, jaundice, and an abnormally enlarged spleen (splenomegaly).[rarediseases.org]
  • Some people have jaundice and abdominal fullness or discomfort. Diagnosis usually requires special hemoglobin tests. Mild thalassemia may not require treatment, but severe thalassemia may require bone marrow transplantation.[merckmanuals.com]
  • They may include severe anemia and other health problems, such as: A pale and listless appearance Poor appetite Dark urine (a sign that red blood cells are breaking down) Slowed growth and delayed puberty Jaundice (a yellowish color of the skin or whites[web.archive.org]
Hepatosplenomegaly
  • They have severe anemia and hepatosplenomegaly. Untreated children have severe failure to thrive and shortened life expectancy. Transfusion programs and chelation therapy allow for normal growth and development.[meddean.luc.edu]
  • Diagnostic methods Diagnosis is suspected in infants younger than 2 years of age with severe microcytic anemia, mild jaundice and hepatosplenomegaly.[orpha.net]
  • Additional signs and symptoms can include severe anemia, an enlarged liver and spleen (hepatosplenomegaly), heart defects, and abnormalities of the urinary system or genitalia.[rxlist.com]
  • Slight hepatosplenomegaly and possibly a recurrent jaundice in a mild form can be present. Also, target cells can be observed in the blood count.[lecturio.com]
  • Patients may also present with growth retardation, skeletal abnormalities, and hepatosplenomegaly. With regular blood transfusions, life expectancy is good. Without transfusions, life expectancy is limited to a few years.[openanesthesia.org]
Hepatomegaly
  • The 5-year probabilities of OS and DFS in older patients (age 7 years) without hepatomegaly were 86% (95% CI, 72%-96%) and 83% (95% CI, 67%-94%), respectively. Figure 1 Probability of OS by age and hepatomegaly.[doi.org]
  • The presence of hepatomegaly was a statistically significant predictor for poor physical QOL (OR   8.5, p   0.02). Household income was the statistically significant predictor for poor emotional QOL (OR   5.03, p   0.04).[ncbi.nlm.nih.gov]
  • They also have massive hepatomegaly due to heart failure and extramedullary hematopoiesis. An excess of hemoglobin Bart’s, which is unable to carry oxygen effectively, is usually present.[emedicine.medscape.com]
  • Feeding problems, diarrhea, irritability, recurrent bouts of fever, and progressive enlargement of the abdomen caused by splenomegaly and hepatomegaly may occur.[orpha.net]
  • Hepatomegaly related to significant extramedullary hematopoiesis is typically found. Patients who have received blood transfusions may have hepatomegaly or chronic hepatitis due to iron overload.[emedicine.medscape.com]
Osteoporosis
  • BPs and in particular, zolendronate, were quite effective in the treatment of osteoporosis. These findings suggested that bisphosphonates are still a front-line treatment of osteoporosis in TM.[ncbi.nlm.nih.gov]
  • KEYWORDS: Calcium transport; Iron transport; Osteoporosis; Thalassemia; Vitamin D[ncbi.nlm.nih.gov]
  • Clinical presentations include growth impairment, rickets-like features, back pain, spinal deformities, any sign of nerve compression, severe osteoporosis, and fragility fractures.[ncbi.nlm.nih.gov]
  • Osteoporosis Many people who have thalassemias have bone problems, including osteoporosis (OS-te-o-po-RO-sis). This is a condition in which bones are weak and brittle and break easily.[web.archive.org]
  • Bachrach, Osteoporosis in Childhood and Adolescence, Osteoporosis, 10.1016/B978-0-12-415853-5.00043-1, (1037-1086), (2013).[doi.org]
Back Pain
  • Abstract We report a case of a thalassemia major male patient with back pain associated to severe weakness in lower extremities resulting in the ability to ambulate only with assistance.[ncbi.nlm.nih.gov]
  • Clinical presentations include growth impairment, rickets-like features, back pain, spinal deformities, any sign of nerve compression, severe osteoporosis, and fragility fractures.[ncbi.nlm.nih.gov]
Frontal Bossing
  • bossing (due to bone marrow expansion) Delayed pneumatization of sinuses Marked overgrowth of the maxillae Ribs and long bones becoming boxlike and convex Premature closure of epiphyses resulting in shortened limbs Compression fracture of the spine ([emedicine.medscape.com]
  • When facial bones are affected it can result in distinctive facial features including an abnormally prominent forehead (frontal bossing), full cheek bones (prominent malar eminence), a depressed bridge of the nose, and overgrowth (hypertrophy) of the[rarediseases.org]
  • Bony abnormalities, such as frontal bossing, prominent facial bones, and dental malocclusion, are usually striking. Severe pallor, slight to moderately severe jaundice, and marked hepatosplenomegaly are almost always present.[emedicine.medscape.com]
  • bossing, cortical thinning, dilation of the medullary cavities, prominence of the zygomatic bones, and shortening of the long bones, can also be seen in patients with thalassemia intermedia.[emedicine.medscape.com]
Headache
  • At the age of 18, the described patient presented with progressively worsening lethargy, headaches, dizziness, syncope and Raynaud's phenomenon.[ncbi.nlm.nih.gov]
  • Side effects include headache, nausea (feeling sick to the stomach), vomiting, diarrhea, joint pain, and tiredness. Folic Acid Supplements Folic acid is a B vitamin that helps build healthy red blood cells.[web.archive.org]
  • These conditions provoke pallor or jaundice, fatigue, headaches and dizziness. Patients may have breathing difficulties under exercise.[symptoma.com]
Dizziness
  • At the age of 18, the described patient presented with progressively worsening lethargy, headaches, dizziness, syncope and Raynaud's phenomenon.[ncbi.nlm.nih.gov]
  • These conditions provoke pallor or jaundice, fatigue, headaches and dizziness. Patients may have breathing difficulties under exercise.[symptoma.com]
  • Severe anemia develops and is associated with fatigue, weakness, shortness of breath, dizziness, headaches, and yellowing of the skin, mucous membranes and whites of the eyes (jaundice).[rarediseases.org]
  • These may include: Pale skin Crankiness Weakness Tiredness Shortness of breath Trouble doing normal amounts of exercise (exercise intolerance) Fast heartbeat Dizziness or fainting Yellowing of the eyes, skin, or mouth, and dark urine (jaundice) Slowed[fairview.org]

Workup

Initially, laboratory analyses of blood tests are realized. In fact, pathological findings from the patient's hemogram often prompt a tentative diagnosis of thalassemia. Usually, the disease is associated with microcytosis, hypochromia and anemia. The mean corpuscular volume (MCV) is reduced, i.e., values are below 70 fl and 80 fl in children and adults, respectively [5]. Erythrocytes are loaded with few hemoglobin, and mean corpuscular hemoglobin concentrations (MCHC) are lower than physiological values (reference range is 30-35 g/dl). Total hemoglobin concentrations are typically below 10 g/dl in thalassemia intermedia, and below 7 g/dl in thalassemia major (physiological range is 12-17 g/dl). Red blood cell distribution width may be enhanced, and blood films may reveal anisocytosis and poikilocytosis. While thrombocytic counts are generally unaltered, leukocytosis may be detected. Thrombocytopenia and leucopenia may be observed in patients presenting with splenomegaly.

Hemoglobin electrophoresis is needed to assess the composition of hemoglobin with regards to its polypeptide chains. Findings are usually diagnostic for or β-thalassemia. However, in α-thalassemia, molecular biological techniques have to be applied to identify the mutated gene(s) in an individual patient. Polymerase chain reactions may also be carried out to detect specific genetic mutations.

Microcytic Anemia
  • On the basis of limited descriptions in the literature, the disease is reported as a mild microcytic anemia with an uncomplicated course.[ncbi.nlm.nih.gov]
  • METHODS: The study was done on two adult Thai patients (P1 and P2) who had hypochromic microcytic anemia. Hb analysis was carried out using high performance liquid chromatography (HPLC) and capillary electrophoresis (CE).[ncbi.nlm.nih.gov]
  • […] thal·as·se·mia \ ˌtha-lə-ˈsē-mē-ə \ : any of a group of inherited disorders of hemoglobin synthesis (such as Cooley's anemia ) that are marked by mild to severe hypochromic and microcytic anemia, result from the partial or complete failure in production[merriam-webster.com]
  • KEYWORDS: alpha; cut-off; deletional; differential diagnosis; microcytic anemia; number of genes; thalassemia[ncbi.nlm.nih.gov]
  • KEYWORDS: hypochromic microcytic anemia; reduced beta/alpha synthesis ratio[ncbi.nlm.nih.gov]
Heinz Bodies
  • Six rare mutations, despite being heterozygote, showed hemolytic anemia which is also called, "dominant-type thalassemia", and some of them demonstrated Heinz bodies in the red blood cells.[ci.nii.ac.jp]
  • bodies from HbH β-thalassemia minor target, hypochromic, microcytic cells β-thalassemia major nucleated RBCs target, hypochromic, microcytic cells Hemoglobin gel-electrophoresis α-thalassemia trait normal 3 gene deletion α-thalassemia HbH (β,β,β,β) 4[medbullets.com]
  • These inclusions are termed Heinz bodies, depicted below.[emedicine.medscape.com]
  • Crystal violet or new methylene blue supravital stains will detect Heinz bodies (precipitated Hgb H). If all four a genes are deleted, death in utero results. The RBCs contain only Bart's hemoglobin a tetramer of g chains.[med-ed.virginia.edu]
Poikilocytosis
  • At major thalassemia and intermediate thalassemia, hypochromasia and poikilocytosis are more distinct. Reticulocytes, LDH and bilirubin are increased; haptoglobin is decreased.[lecturio.com]
  • Red blood cell distribution width may be enhanced, and blood films may reveal anisocytosis and poikilocytosis. While thrombocytic counts are generally unaltered, leukocytosis may be detected.[symptoma.com]
  • Beginning in the first year of life the PBS shows severe anisocytosis and poikilocytosis, targets, elliptocytes, teardrops, and NRBCs.[med-ed.virginia.edu]
  • Peripheral blood smear will show hypochromia, microcytosis, anisocytosis, poikilocytosis, and rare nucleated RBCs (erythroblasts).[clinicaladvisor.com]
Anisopoikilocytosis
  • Blood analysis shows reduced Hb levels ( 7 g/dl), mean corpuscular volume (MCV) 50 70 fl, and mean corpuscular Hb (MCH) 12 20 pg, anisopoikilocytosis and presence of erythroblasts in the peripheral blood smear.[orpha.net]
  • Peripheral smear from a patient with beta-zero thalassemia major showing more marked microcytosis (M) and anisopoikilocytosis (P) than in thalassemia minor. Target cells (T) and hypochromia are prominent.[emedicine.medscape.com]
  • Peripheral smear shows target cells, teardrop RBCs, polychromasia, moderate anisopoikilocytosis, and basophilic stippling. Hemoglobin electrophoresis is normal in alpha thalassemia minima and minor.[clinicaladvisor.com]
Hepatocellular Carcinoma
  • KEYWORDS: Hepatitis B virus (HBV); hepatitis C virus (HCV); hepatocellular carcinoma (HCC); iron overload; liver iron concentration (LIC); thalassemia[ncbi.nlm.nih.gov]
  • Hepatocellular carcinoma in thalassaemia: an update of the Italian Registry.[ncbi.nlm.nih.gov]
  • Concomitant viral hepatitis poses further increased risk of hepatocellular carcinoma and cirrhosis. Most thalassemia patients older than 25 years are infected with hepatitis C (HCV).[clinicaladvisor.com]
  • With increasing length of survival, hepatocellular carcinoma is becoming an increasing problem. [ 15 ] Desferrioxamine can cause toxicity: Local reaction at the site of injection can be severe.[patient.info]

Treatment

No specific therapy is required thalassemia minor. In contrast, thalassemia major and possible thalassemia intermedia patients may be dependent on regular, treatment throughout life.

  • Blood transfusions are realized regularly due to thalassemia major, but may be required by thalassemia intermedia patients during anemic crises or in case of failure to thrive and growth retardation. Ideally, hemoglobin levels should be maintained above 10 g/dl. Patients should understand the necessity of adhering to a determined schedule of blood transfusions in order to raise life quality and life expectancy.
  • Chelation therapy is indicated to prevent secondary iron overload, particularly in patients receiving regular transfusions of blood products. Nevertheless, regular monitoring is also recommended to recognize iron overload in patients who don't depend on blood transfusions.
  • Dietary supplementation with folic acid compensates for folate deficiency.
  • Eventually, splenomegaly may cause splenic sequestration, thrombocytopenia and leucopenia. Affected persons may benefit from splenectomy, but this procedure is not without risks [10].
  • Hematopoietic stem cell transplantation may be curative, but the application of this therapeutic approach is limited by the condition of the thalassemia patient and the availability of a matching donor.

Prognosis

For patients presenting with asymptomatic thalassemia, the prognosis is excellent. However, with increasing severity of the disease, morbidity and mortality augment. The life expectancy of an individual patient also depends on their access to health care services. People suffering from thalassemia intermedia or major may require transfusions of blood products, and anemic and aplastic crises are life-threatening if medical attention is not provided in a timely manner. Furthermore, secondary iron overload, anemia and subsequent heart failure may be fatal. Thalassemia patients are at higher risks of developing cholelithiasis, urolithiasis and gout. It is not uncommon to observe growth retardation in affected individuals. Certain types of thalassemia are incompatible with life. α-thalassemia major, for instance, causes hydrops fetalis and death in utero.

Etiology

Thalassemia results from an insufficient synthesis of functional hemoglobin and this condition is provoked by a wide variety of mutations to be found on chromosomes 11 and 16. Genes encoding for all types of globin chains, i.e., for Hbα, Hbβ, Hbγ and Hbδ, are located on these chromosomes, and this also applies to their respective regulatory sequences. In this context, a total of six genes needs to be considered when discussing thalassemia, and distinct forms of this disease are defined accordingly:

  • β-thalassemia is the most common type of thalassemia. In affected individuals, the synthesis of Hbβ is disturbed. Mutations affect gene HBB on chromosome 11.
  • There are four genes encoding for Hbα, each one HBA1 and HBA2 inherited from mother and father. Gene defects induce α-thalassemia, but the severity of the disease varies largely: Patients who carry one or two affected genes don't generally show any symptoms, but dysfunction of all four genes is lethal in utero.
  • Thalassemia due to mutation of genes HBG1, HBG2 or HBD are less common. Some people carry mutations of several genes encoding for globin chains and are consequently diagnosed with complex thalassemia, e.g., with δβ- or γδβ-thalassemia [3] [4].

All known mutations provoking thalassemia are inherited as an autosomal recessive trait.

Epidemiology

Thalassemia is a rather common disease, and occurs in about 1 in 2,500 live births [5]. Incidence rates are even higher among people of African, Asian or Middle Eastern decent, and in determined ethnicities, more than a third of the population carries thalassemia-related mutations [6] [7]. Geographical differences regarding thalassemia incidence very clearly show how natural selection works: Thalassemia provides partial protection against malaria and thus confers an evolutionary advantage to carriers in subtropical and tropical regions, but the opposite is the case in areas without prevalence of this parasitic disease. In general, β-thalassemias predominate, but the ratio between prevalences of α- and β-thalassemia is higher in Africa and Southeast Asia than in other parts of Asia and the Middle East.

Despite thalassemia being a genetic disorder, symptom onset rarely occurs during the first year of life. This is due to an ongoing synthesis of fetal hemoglobin during infancy. In rare cases, production of fetal hemoglobin does not cease until the age of a few years, and this may mask even severe forms of thalassemia.

Females and males are affected equally.

Sex distribution
Age distribution

Pathophysiology

Every hemoglobin molecule consists of four globin chains. In patients aged one year and older, about 97% of total hemoglobin correspond to hemoglobin A1, which is constituted of each two Hbα and Hbβ. The remaining 3% almost exclusively correspond to hemoglobin A2, and this form of hemoglobin is composed by each two Hbα and Hbδ. Other hemoglobin variants play important roles only during fetal and early postnatal development.

Moreover, each globin chain is associated with a heme group that, in turn, contains a ferrous ion. In pulmonary capillaries, iron-containing heme groups bind oxygen and carry it to all kinds of tissues. If this process is disturbed by either qualitative or quantitative alterations of hemoglobin synthesis, oxygen supply to dependent cells would be impaired. Patients suffering from thalassemia dispose of insufficient functional hemoglobin and thus present with hypochromic microcytic anemia.

In an attempt to compensate for a decreased synthesis of Hbα and Hbβ in α- and β-thalassemia, respectively, production of the other globin chain is stimulated in excess [8]. Additionally, Hbγ and Hbδ synthesis may be altered. Such imbalances in globin chain composition provoke the formation of inclusion bodies in circulating erythrocytes, augment oxidative stress and predispose for hemolysis. Premature lysis of erythrocytes further contributes to anemia and shortage of oxygen supply.

If an individual disposes of functional copies of genes HBA1, HBA2 or HBB, the aforedescribed pathophysiological events occur to minor degrees and patients may either be completely asymptomatic or merely show hematological alterations without experiencing any symptoms. Such forms of thalassemia are typically classified as minor thalassemia. Other patients are diagnosed with thalassemia intermedia or major, but there is a smooth transition between all those types of hemoglobinopathy.

Prevention

Thalassemia is a genetic disorder inherited with an autosomal recessive trait. Thus, patients with a family history of thalassemia may benefit from genetic counseling. Prenatal diagnosis of thalassemia and other hemoglobinopathies can be realized. Nowadays, non-invasive, early applicable methods are available to this end [11].

Summary

Thalassemia is a general term referring to different genetic disorders that are all associated with a disturbed hemoglobin synthesis.

A functional hemoglobin molecule consists of four polypeptide chains - generally, each two identical α and β chains (Hbα and Hbβ, respectively) - and four iron-containing heme groups. Only a minor share of human hemoglobin molecules contains γ or δ globin chains (Hbγ and Hbδ, respectively). Genes located on chromosomes 11 and 16 encode for all these globin chains, and mutations of those genes trigger hemoglobinopathies. Both coding sequences and regulatory elements can be affected by mutations and accordingly, two types of hemoglobinopathies are distinguished: Structural hemoglobinopathies, which are associated with dysfunctional hemoglobin due to coding sequence alterations; and thalassemia syndromes, characterized by an insufficient production of functional hemoglobin owing to defective regulation of globin synthesis [1].

As has been implied in the previous paragraph, there is no one gene defect that provokes thalassemia. In fact, several hundred mutations have been related with this disease so far, and while their respective incidence varies largely, it may be surprising to read about high prevalence rates of thalassemia in subtropical and tropical regions of almost all continents. This is due to the fact that carriers of thalassemia-associated mutations are partially protected from the most severe form of malaria, induced by infection with Plasmodium falciparum. More recent studies suggest that protection is not only conferred for malaria tropica, but also for uncomplicated forms of this disease [2].

Patient Information

Thalassemia is a type of hemoglobinopathy, i.e., a condition that affects the ability of hemoglobin and red blood cells to supply all tissues with oxygen. It is a genetic disorder inherited with an autosomal recessive trait. In simple terms, this means that a child will only develop thalassemia if they inherit a mutated gene from both parents.

Under physiological conditions, oxygen is bound to hemoglobin molecules in pulmonary capillaries. In thalassemia patients, however, the capacity for oxygen transport is significantly diminished, since reduced quantities of functional hemoglobin are synthesized. In detail, a hemoglobin molecule consists of distinct protein chains, mainly α and β chains, and thus, thalassemia may result from a disturbed synthesis of either type of chain. As soon as the precise pathomechanism is identified, a patient may be diagnosed with α- or β-thalassemia or less common forms of the disease.

The majority of people carrying gene variants associated with thalassemia do not experience any symptoms. In such cases, thalassemia might be suspected upon laboratory analyses of blood samples realized for any other reasons. More severe forms of thalassemia are characterized by anemia and premature death of red blood cells. These conditions provoke pallor or jaundice, fatigue, headaches and dizziness. Patients may have breathing difficulties under exercise. Anemic crises may be triggered by infection, folate deficiency or pregnancy, and are associated with an acute exacerbation of the aforementioned symptoms.

Mild forms of thalassemia don't require any treatment. Patients diagnosed with thalassemia of intermediate severity may suffer anemic crises and may need occasional transfusions of blood products. Severe thalassemia is a life-threatening disease and affected individuals need to adhere to a strict schedule of regular transfusions. Additionally, drugs may be prescribed to compensate for folate deficiency and possible secondary iron overload.

References

Article

  1. Higgs DR. The molecular basis of alpha-thalassemia. Cold Spring Harb Perspect Med. 2013; 3(1):a011718.
  2. Enevold A, Lusingu JP, Mmbando B, et al. Reduced risk of uncomplicated malaria episodes in children with alpha+-thalassemia in northeastern Tanzania. Am J Trop Med Hyg. 2008; 78(5):714-720.
  3. Cardiero G, Prezioso R, Dembech S, et al. Identification and molecular characterization of a novel 163 kb deletion: The Italian (gammadeltabeta)(0)-thalassemia. Hematology. 2016; 21(5):317-324.
  4. Cao A, Kan YW. The prevention of thalassemia. Cold Spring Harb Perspect Med. 2013; 3(2):a011775.
  5. Muncie HL, Jr., Campbell J. Alpha and beta thalassemia. Am Fam Physician. 2009; 80(4):339-344.
  6. Than AM, Harano T, Harano K, et al. High incidence of 3-thalassemia, hemoglobin E, and glucose-6-phosphate dehydrogenase deficiency in populations of malaria-endemic southern Shan State, Myanmar. Int J Hematol. 2005; 82(2):119-123.
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Last updated: 2017-08-09 17:37