Thalassaemia

Overview

Thalassaemias are inherited disorders in which too little of one globin chain is made. Normally alpha and beta chains are made in a 1 : 1 ratio. In thalassaemia the balance is lost; the excess partner chain precipitates inside red cell precursors, killing many of them in the marrow (ineffective erythropoiesis) and shortening the life of those that reach the blood (haemolysis).

Thalassaemia is very common in Pakistan. Beta thalassaemia major is a major cause of transfusion dependence in children, and carrier screening before marriage and in pregnancy is promoted.

Normal haemoglobins

• Alpha genes: two on each chromosome 16 (four in total).
• Beta, gamma and delta genes: chromosome 11 (one beta gene on each).

Types and genetics

Beta thalassaemia

• Caused mostly by point mutations (over 200 known) affecting transcription, splicing or translation.
• β0: no beta chain made. β+: reduced beta chain.
• Inheritance: autosomal recessive.

NTDT happens when the excess alpha chains are reduced, for example by co-inheriting alpha thalassaemia or by persistent HbF production that "mops up" alpha chains.

Alpha thalassaemia

• Caused mostly by gene deletions. Four alpha genes are normally present.

• Two-gene deletions may sit on the same chromosome (cis, common in South-East Asia) or on opposite chromosomes (trans). Two cis carriers can have a hydropic baby.

Pathophysiology of beta thalassaemia major

1. No or little beta chain → excess alpha chains precipitate in erythroblasts.
2. Most erythroblasts die in the marrow (ineffective erythropoiesis); those released are destroyed in the spleen (haemolysis).
3. Severe anaemia drives erythropoietin → massive marrow expansion (bone deformity) and extramedullary haemopoiesis (liver and spleen enlarge).
4. Ineffective erythropoiesis releases erythroferrone, which suppresses hepcidin, so gut iron absorption rises. Add transfusions and iron overload follows.
5. HbF protects at birth; symptoms start at 3–6 months as gamma chain production falls.

Clinical presentation and physical signs

Thalassaemia trait

• Usually no symptoms; found on a routine blood count or in pregnancy.
• Often mistaken for iron deficiency and given iron for years.

Beta thalassaemia major (TDT)

Presents in the first year of life with:

• Pallor, poor feeding, failure to thrive, recurrent infections.
• Hepatosplenomegaly (often massive splenomegaly).
• Thalassaemic facies: frontal bossing, prominent maxilla and cheekbones ("chipmunk face"), depressed nasal bridge, dental malocclusion.
• Jaundice (mild) and pigment gallstones.
• Skull X-ray: "hair-on-end" (crew-cut) appearance from marrow expansion; widened marrow and thin cortex in hand bones.
• Growth failure and delayed puberty.

Lab investigations and diagnosis

Blood count and film

• Low MCV and MCH, often very low for the degree of anaemia.
• Red cell count normal or high (unlike iron deficiency).
• RDW usually normal in trait (cells are uniformly small). In iron deficiency RDW is raised.
• Film: microcytic hypochromic cells, target cells, basophilic stippling; in major also nucleated red cells and marked poikilocytosis.
• Reticulocytes raised in major.

Mentzer index

MCV (fL) divided by red cell count (× 10^12/L). A value below about 13 suggests thalassaemia trait; above 13 suggests iron deficiency. It is only a screening clue; confirm with ferritin and electrophoresis.

Iron studies

• Ferritin normal (or high in major from overload).
• Serum iron and TIBC normal in trait.

Haemoglobin electrophoresis or HPLC (diagnostic)

• DNA analysis identifies the mutation and is used for prenatal diagnosis (chorionic villus sampling in the first trimester).

Trait versus iron deficiency

Complications

From the disease

• Bone deformity, osteoporosis, fractures.
• Hypersplenism (worsening anaemia, low platelets and white cells).
• Pigment gallstones.
• Leg ulcers, thrombosis and pulmonary hypertension (especially NTDT after splenectomy).
• Aplastic crisis with parvovirus B19.
• Extramedullary haemopoietic masses (paraspinal, can compress the cord).

From transfusion and iron overload (transfusion haemosiderosis)

• Heart: cardiomyopathy and arrhythmias, the leading cause of death.
• Liver: fibrosis and cirrhosis.
• Endocrine: diabetes, hypothyroidism, hypoparathyroidism, hypogonadism (delayed puberty), growth failure.
• Skin bronze pigmentation.
• Transfusion-transmitted infection (hepatitis B, hepatitis C, HIV) and alloimmunisation.
• Yersinia enterocolitica infection in iron-loaded patients on desferrioxamine.

Management

Thalassaemia trait

• No treatment needed. Do not give iron unless iron deficiency is proven.
• Genetic counselling: test the partner. If both parents carry beta trait, each pregnancy carries a 25% risk of thalassaemia major, 50% of a carrier child and 25% of a child with normal genes. Offer prenatal diagnosis.

Transfusion-dependent thalassaemia

1. Regular transfusion of packed red cells, roughly every 4–6 weeks, to keep the Hb above 100 g/L. This suppresses ineffective erythropoiesis, prevents bone changes and allows normal growth. Use extended-phenotype matched, leucocyte-depleted blood.
2. Iron chelation (start once ferritin and transfusion burden rise):

• Monitor iron load with serum ferritin and MRI (T2\*) of heart and liver.

1. Folic acid supplements long term.
2. Splenectomy only for hypersplenism or rising transfusion need; delay until after age 6; give vaccines (pneumococcal, Hib, meningococcal) beforehand and lifelong penicillin after.
3. Endocrine and bone care: monitor growth and puberty, glucose, thyroid, calcium; treat osteoporosis.
4. Allogeneic haemopoietic stem cell transplant from an HLA-matched sibling is the only established cure; best results in young, well-chelated children without liver damage.
5. HbF inducers such as hydroxycarbamide help some NTDT patients. Gene therapy is emerging.

Non-transfusion-dependent thalassaemia

• Folic acid; transfuse during infection, pregnancy or growth failure.
• Watch for iron overload even without transfusion (raised gut absorption); chelate if needed.

Quick revision

• Beta: chromosome 11, point mutations. Alpha: chromosome 16, deletions.
• Trait: very low MCV, high RBC count, normal RDW, normal ferritin, HbA2 above about 3.5%.
• Iron deficiency hides HbA2: correct iron first.
• Major: presents at 3–6 months; hepatosplenomegaly, chipmunk face, hair-on-end skull; HbF very high, HbA absent or low.
• HbH (β4) = 3 alpha genes deleted; Hb Barts (γ4) = 4 deleted, hydrops fetalis.
• Transfuse every 4–6 weeks to Hb above 100 g/L; chelate (desferrioxamine, deferasirox, deferiprone).
• Death mainly from iron overload cardiomyopathy.
• Cure: HLA-matched sibling stem cell transplant.

Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Pathoma: Fundamentals of Pathology; Katzung's Basic and Clinical Pharmacology).

FAQ