Thalassemia

Thalassemia, also called Mediterranean anemia, is a group of hereditary microcytic hemolytic anemias. The common feature is that globin-gene defects reduce or abolish synthesis of one or more globin peptide chains in hemoglobin, altering hemoglobin composition. Clinical symptoms vary in severity; most present as chronic progressive hemolytic anemia.

Common Symptoms

Hemosiderosis; weakness; osteoporosis; hepatosplenomegaly

Causes and Pathogenesis

Etiology: globin-gene deletion or point mutation. There are 4 globin peptide chains (alpha, beta, gamma, delta), each encoded by its own gene; gene deletions/point mutations cause various chain-synthesis defects, altering hemoglobin composition. Thalassemia is divided into alpha, beta, delta-beta and delta types; beta and alpha are most common. Beta-thalassemia: human beta-globin gene cluster at 11p15.5; caused mainly by point mutations, rarely gene deletion. Gene deletions and some point mutations fully suppress beta-chain production (beta0 thalassemia); other point mutations partially suppress it (beta+). Over 100 mutations known, 28 in China; 6 common: (1) beta41-42 (-TCTT) ~45%; (2) IVS-II-654 (C->T) ~24%; (3) beta17 (A->T) ~14%; (4) TATA box -28 (A->T) ~9%; (5) beta71-72 (+A) ~2%; (6) beta26 (G->A, HbE) ~2%. Beta-thalassemia major is beta0/beta+ homozygote or beta0/beta+ double heterozygote; beta-chain synthesis is completely/near-completely suppressed, HbA decreases/disappears, excess alpha chains combine with gamma chains to form HbF (alpha2gamma2), markedly raising HbF; high HbF oxygen affinity causes tissue hypoxia. Excess alpha chains deposit in normoblasts/RBCs as alpha-chain inclusions on the RBC membrane, making cells rigid; most are destroyed in marrow causing ineffective erythropoiesis. Some inclusion-bearing RBCs mature and enter peripheral blood but are destroyed in microcirculation; inclusions also increase membrane permeability, shortening RBC life. Children have chronic hemolytic anemia; anemia/hypoxia stimulates erythropoietin and marrow expansion causing bone changes; anemia increases intestinal iron absorption plus repeated transfusions cause tissue iron overload and hemosiderosis. Thalassemia minor is beta0/beta+ heterozygote with mild beta-chain reduction and minimal pathophysiology. Thalassemia intermedia is double heterozygote of beta+ or certain variants, pathophysiology between major and minor. Alpha-thalassemia: human alpha-globin cluster at 16pter-p13.3; 2 alpha genes per chromosome, 4 total. Most alpha-thalassemia is from gene deletion, rarely point mutation. Deletion/defect of one alpha gene on one chromosome = alpha+ thalassemia; deletion of both alpha genes on each chromosome = alpha0 thalassemia. Alpha-thalassemia major is alpha0 homozygote with all 4 alpha genes deleted; no alpha chains, so HbA/HbA2/HbF all decrease; fetus makes abundant gamma chains forming gamma4 (Hb Bart's). Hb Bart's has extremely high oxygen affinity, causing tissue hypoxia and hydrops fetalis. Intermedia alpha-thalassemia is alpha0/alpha+ heterozygote with 3 alpha-gene deletions; only small alpha chains produced, excess beta chains form HbH (beta4). HbH has high oxygen affinity and is unstable, denaturing in RBCs to form inclusions, rigidifying membranes and shortening RBC life. Minor alpha-thalassemia is alpha+ homozygote or alpha0 heterozygote with 2-gene deletion and mild pathophysiology. Silent alpha-thalassemia is alpha+ heterozygote with 1-gene deletion and very mild pathophysiology.

Treatment

Drug therapy, supportive therapy

Preventive Measures

Daily prevention: 1. Population screening and genetic counseling, premarital guidance to avoid marriages between carriers; prenatal genetic diagnosis in early pregnancy can detect severe beta/alpha thalassemia fetuses and allow termination, preventing hydrops fetalis and births of major-thalassemia patients - currently the most effective prevention. 2. Thalassemia carriers look/grow normally. 3. Vitamin supplementation as usual; because carriers are hard to recognize, they are often wrongly given iron as a blood tonic - be cautious. 4. Premarital check: partners should be tested for thalassemia carrier status; if positive, special prenatal care is needed. Health education: 1. Severe thalassemia is hard to treat and lifelong transfusion is very costly; stem-cell transplant needs a matched donor and severe infants may not wait. Thus the most effective prevention is preventing birth of severe patients, especially in high-prevalence areas. 2. Ideally know carrier status before pregnancy/marriage: both partners get screened at a 3A hospital; if abnormal, go to an approved gene lab for confirmation with a small venous sample. If either partner has thalassemia, doctors explain risks and the couple decides carefully. 3. If one/both partners are patients and the wife is pregnant, monitor the fetus at an approved prenatal-diagnosis hospital. If the fetus is normal or minor thalassemia, pregnancy can continue. Hb Bart's hydrops fetalis (most severe alpha-thalassemia) is detectable by ultrasound in mid-pregnancy; severe beta-thalassemia often has no ultrasound abnormality, so early fetal genetic testing is essential. If severe disease is confirmed, doctors recommend termination to prevent birth of a severely affected child.

Department to Visit

It is recommended to visit the Hematology department; an appointment can be booked on this platform before the visit.

Warm reminder: The above information is for health science reference only and cannot replace professional medical diagnosis. If you have related symptoms, please seek medical attention at a regular hospital promptly.