Thalassemia — Types, Causes, Diagnosis & Treatment Guide — Symptoms, Causes & Treatment | MyMedicPlus

Thalassemia is a group of inherited haemoglobin disorders caused by mutations in the genes encoding alpha or beta globin chains of haemoglobin, resulting in reduced or absent production of one or both globin chain types. Haemoglobin A (the predominant adult haemoglobin) consists of two alpha and two beta globin chains. Imbalanced globin chain production causes ineffective erythropoiesis (abnormal red blood cell production in the bone marrow), haemolytic anaemia (premature destruction of red blood cells), and compensatory extramedullary haematopoiesis. Thalassemia is the world's most common single-gene disorder — approximately 100 million people carry thalassemia traits (heterozygous carriers) globally, predominantly in a 'thalassemia belt' spanning the Mediterranean basin, Middle East, Indian subcontinent, and Southeast Asia. Approximately 60,000-100,000 new cases of severe thalassemia are born annually. Alpha thalassemia is most prevalent in Southeast Asia, China, and Africa; beta thalassemia is most prevalent in Mediterranean countries (Greece, Cyprus, Italy, Sardinia), the Middle East, Pakistan, and India. Thalassemia major (transfusion-dependent) is a life-threatening condition requiring comprehensive haematology management; thalassemia trait (heterozygous) is asymptomatic and requires no treatment but genetic counselling.

Beta thalassemia is caused by over 300 mutations in the HBB gene (encoding beta-globin), predominantly point mutations causing abnormal splicing, premature stop codons, or transcription defects. Beta thalassemia major (Cooley's anaemia): homozygous or compound heterozygous mutations causing absent (beta-zero) or severely reduced (beta-plus) beta-globin production; excess unpaired alpha chains precipitate, causing intramedullary destruction of erythroblasts (ineffective erythropoiesis) and haemolysis. Beta thalassemia intermedia: milder mutations — symptoms between trait and major. Beta thalassemia trait (minor): heterozygous carrier — typically asymptomatic with mild microcytic anaemia. Alpha thalassemia is caused predominantly by large deletions of the alpha-globin genes (HBA1 and HBA2 on chromosome 16 — each individual has two alpha genes per chromosome, four total). Spectrum of alpha thalassemia from mildest to most severe: silent carrier (one gene deleted — asymptomatic); alpha thalassemia trait (two genes deleted — mild microcytic anaemia); HbH disease (three genes deleted — moderate haemolytic anaemia, splenomegaly — requires monitoring and occasional transfusion); haemoglobin Bart's hydrops fetalis (four genes deleted — incompatible with life — severe fetal anaemia, hydrops, and stillbirth or early neonatal death). Genetic counselling: two carrier parents have 25% chance per pregnancy of an affected child — the basis of national prevention programmes.

Beta thalassemia major presents in the first year of life, after fetal haemoglobin (HbF) switches to adult HbA: severe hypochromic microcytic anaemia (haemoglobin typically 5-7 g/dL without transfusion); pallor, failure to thrive, poor feeding, and progressive hepatosplenomegaly (from extramedullary haematopoiesis — the bone marrow expansion attempts to compensate). Without regular transfusions, progressive skeletal deformities develop: characteristic 'chipmunk' or 'thalassaemic facies' (frontal bossing, prominence of malar eminences, maxillary overgrowth displacing teeth) from expansion of marrow-filled diploe; 'hair-on-end' appearance on skull X-ray from marrow expansion. Other features: jaundice, growth retardation, delayed puberty (iron overload affecting pituitary gonadotropins), gallstones, and increased infection susceptibility. Beta thalassemia intermedia: symptoms vary widely — moderate anaemia (Hb 7-10 g/dL) with variable transfusion dependence; splenomegaly; iron overload from increased gastrointestinal absorption; bone complications. Iron overload (haemosiderosis): iron deposits in the heart (cardiomyopathy — leading cause of death in undertreated thalassemia major), liver (cirrhosis, liver failure), endocrine organs (diabetes mellitus, hypothyroidism, hypogonadism, hypoparathyroidism, growth failure). Serum ferritin levels above 2,500 ng/mL and liver iron concentration above 7 mg/g dry weight signal clinically significant iron overload requiring intensified chelation.

Complete blood count (CBC): severe microcytic hypochromic anaemia (low MCV typically 50-70 fL, low MCH, low Hb); elevated RBC count relative to low Hb (low MCHC); elevated RDW (red cell distribution width). Peripheral blood film: microcytes, hypochromia, target cells, nucleated RBCs (normoblasts — hallmark of severe thalassemia), and teardrop cells. Haemoglobin electrophoresis / HPLC (high-performance liquid chromatography): the gold standard test — identifies haemoglobin fractions. Beta thalassemia trait: elevated HbA2 (above 3.5%) — the diagnostic hallmark. Beta thalassemia major: absent or very low HbA with elevated HbF (up to 98%). HbH disease: HbH fraction visible on HPLC/electrophoresis; Heinz body inclusions on special stain. Hb Barts: identified on electrophoresis in hydrops fetalis. Alpha globin gene analysis (PCR-based): essential for precise alpha thalassemia diagnosis and classification. Iron studies: elevated serum ferritin and transferrin saturation (increased iron absorption in thalassemia). Liver MRI (T2*): quantitative liver iron concentration (LIC) to guide chelation intensity. Cardiac MRI (T2*): cardiac iron assessment — T2* below 20ms indicates cardiac iron loading. Prenatal diagnosis: chorionic villus sampling (CVS) at 11-14 weeks or amniocentesis at 15-20 weeks for molecular diagnosis in at-risk pregnancies identified by carrier screening.

Regular blood transfusion is the cornerstone of beta thalassemia major management — given every 2-4 weeks to maintain pre-transfusion haemoglobin above 9-10.5 g/dL, suppressing ineffective erythropoiesis and its complications, and enabling normal growth and development. Leucodepleted packed red blood cells minimise alloimmunisation (antibody formation against transfused blood — occurs in 10-30%, complicating future transfusion). Iron chelation therapy is essential because each unit of transfused blood contains 200-250 mg iron and the body has no physiological mechanism to excrete excess iron: deferoxamine (Desferal — subcutaneous infusion 8-12 hours, 5-7 days/week — effective but burdensome); deferasirox (Exjade/Jadenu — oral daily tablet/granules — most widely used; monitor renal function and liver function); deferiprone (oral 3 times daily — particularly effective for cardiac iron removal; risk of agranulocytosis — weekly WBC monitoring). Haematopoietic stem cell transplantation (HSCT): the only currently established curative treatment — best outcomes in young patients (under 14 years) with matched sibling donors; event-free survival 80-90% in Pesaro Class I (no hepatomegaly, no portal fibrosis, regular chelation); alternative donor (matched unrelated, haploidentical, cord blood) transplants increasingly available. Luspatercept (Reblozyl — erythroid maturation agent targeting ineffective erythropoiesis): approved for transfusion-dependent beta thalassemia (reduces transfusion burden by 33% in trials). Gene therapy: betibeglogene gene therapies (betibeglogene spartogene/Zynteglo) received approval in 2022 — single infusion of autologous haematopoietic stem cells with viral vector encoding functional beta-globin; achieving transfusion independence in 89% of patients with non-beta-zero mutations at 3 years. Folic acid supplementation; splenectomy for hypersplenism; endocrine replacement for iron overload complications.

Iron overload (haemosiderosis) is the principal long-term complication of transfusion-dependent thalassemia — each unit of blood deposits 200–250 mg of iron and the body has no physiological mechanism to excrete excess iron. Without chelation, iron accumulates in the heart (causing dilated cardiomyopathy and fatal arrhythmias — the leading cause of death in undertreated thalassemia, typically before age 30), liver (cirrhosis and liver failure), and endocrine organs (insulin-dependent diabetes mellitus — 10–15% of poorly chelated patients; hypothyroidism; hypoparathyroidism causing tetany and seizures; hypogonadism causing delayed puberty, infertility, and osteoporosis; growth hormone deficiency). Serum ferritin above 2,500 ng/mL and liver iron concentration above 7 mg/g dry weight (by MRI T2*) signal clinically significant overload requiring intensified chelation. Cardiac MRI T2* below 20 ms indicates cardiac iron loading requiring intensification to prevent fatal cardiomyopathy. Alloimmunisation (antibody formation against donor red cell antigens) occurs in 10–30% of chronically transfused patients, making cross-matching increasingly difficult and complicating future transfusion and haematopoietic stem cell transplantation. Splenomegaly from extramedullary haematopoiesis progresses to hypersplenism (destroying blood cells including transfused cells) — splenectomy significantly increases transfusion requirement and exposes patients to post-splenectomy sepsis risk from encapsulated bacteria. Skeletal complications from marrow hyperexpansion include facial deformities (thalassaemic facies), pathological fractures, and osteoporosis. Gallstones (pigment stones) from chronic haemolysis affect the majority and may require cholecystectomy. Chelation therapy side effects include audiological and ophthalmic toxicity (deferoxamine excess) and renal tubular dysfunction (deferasirox).

Thalassemia prevention is achievable through carrier screening and prenatal diagnosis. National carrier screening programmes have dramatically reduced the birth incidence of thalassemia major — Cyprus reduced new cases to near zero, and Sardinia achieved a 90% reduction through community screening, premarital counselling, and prenatal diagnosis. Universal carrier screening of individuals at high risk (Mediterranean, Middle Eastern, South and Southeast Asian, African descent) or population-wide screening in high-prevalence regions identifies heterozygous carriers. If both partners are carriers (both have thalassemia trait), each pregnancy has a 25% risk of an affected child, 50% chance of a carrier, and 25% chance of being unaffected — genetic counselling informs reproductive choices. Prenatal diagnosis: chorionic villus sampling (CVS) at 11-14 weeks or amniocentesis at 15-20 weeks allows definitive molecular diagnosis of the foetus. Preimplantation genetic testing (PGT): IVF with embryo genetic testing selects unaffected embryos for implantation, avoiding the need for termination of pregnancy. Newborn screening in high-prevalence areas enables early diagnosis and commencement of comprehensive care before complications develop.

Children with known thalassemia major should be seen urgently for: severe pallor, listlessness, or inability to feed that is worse than usual between transfusions — may indicate early haemolytic crisis or infection; fever above 38.5°C — immunocompromised patients (post-splenectomy particularly) are at risk of serious bacterial infections requiring prompt antibiotics; abdominal pain with vomiting (possible gallstone disease or splenomegaly complication); and chest pain or breathlessness (possible cardiac iron overload complication). For new parents: any baby of Mediterranean, Middle Eastern, South Asian, or Southeast Asian heritage who has persistent pallor and jaundice beyond 2 weeks, poor feeding, or failing to gain weight should be investigated for haematological disorders including thalassemia. For carriers: seek genetic counselling before planning a pregnancy to understand reproductive options if you or your partner are a thalassemia carrier — identifying this before pregnancy is far less distressing than diagnosis during pregnancy.