After reading this note you will be able to describe the clinical approach to thalassaemia, recognise key examination findings, interpret the essential investigations, grade severity and outline immediate and definitive management – remembering to verify drug choices, doses and local protocols against the Kenya MoH guideline and your hospital formulary.
Definition
Thalassaemia is a hereditary haemoglobinopathy characterised by reduced or absent synthesis of one or more globin chains of adult haemoglobin (Hb A). The imbalance between α‑ and β‑globin synthesis leads to ineffective erythropoiesis, chronic haemolysis and variable degrees of anaemia.
Anatomy and physiology you need
| Structure | Relevance to thalassaemia |
|---|---|
| Erythroid precursors (bone marrow) | Site of globin chain synthesis; defective synthesis causes apoptosis of precursors (ineffective erythropoiesis). |
| Red cell membrane | Abnormal membrane stability from excess unpaired globin chains → microcytosis, target cells. |
| Spleen | Hyperactive in clearing abnormal red cells → splenomegaly, hypersplenism. |
| Liver | Stores iron; chronic transfusion → secondary iron overload, hepatic fibrosis. |
| Heart | End‑organ target of iron overload → cardiomyopathy, arrhythmias. |
| Endocrine glands | Pituitary, thyroid, pancreas vulnerable to iron deposition → endocrine dysfunction. |
Causes and risk factors
- Genetic mutations
- α‑thalassaemia: deletions or point mutations in HBA1/HBA2 genes.
- β‑thalassaemia: point mutations in HBB gene affecting transcription, splicing or translation.
- Ethnic prevalence – high carrier rates in Nilotic, Bantu and coastal populations of Kenya.
- Consanguinity – increases chance of homozygosity.
- Co‑existing conditions that exacerbate anaemia or iron load
- HIV infection (chronic inflammation, marrow suppression).
- Tuberculosis (chronic disease anaemia, increased transfusion need).
- Malaria (hemolysis, may mask thalassaemia features).
- Rheumatic fever (splenomegaly, anemia of chronic disease).
- Sickle cell disease (compound heterozygosity can modify phenotype).
- Nutritional deficiencies (iron, folate) – worsen anaemia but do not cause thalassaemia.
Pathophysiology
Genetic defect → ↓ synthesis of specific globin chain → excess unpaired chain precipitates → membrane damage → premature red‑cell destruction (hemolysis) → chronic anaemia → marrow expansion → ineffective erythropoiesis → ↑ erythropoietin → bone‑marrow hyperplasia → skeletal deformities.
Chronic transfusions (in severe forms) → iron overload → deposition in liver, heart, endocrine organs → organ dysfunction.
Arrows format
Genetic mutation → ↓ α‑ or β‑globin synthesis → chain imbalance → precipitated globin → red‑cell membrane fragility → hemolysis + ineffective erythropoiesis → chronic anaemia → compensatory marrow expansion → skeletal changes & splenomegaly.
Transfusion dependence → excess iron intake → ferritin ↑ → non‑transferrin‑bound iron → free radical generation → organ toxicity (heart, liver, endocrine).
Clinical features
| Aspect | Key questions / findings | Why it occurs |
|---|---|---|
| Age of onset | “When did you first notice symptoms?” – neonatal jaundice, failure to thrive, or later fatigue? | β‑thalassaemia major presents in the first 2 years; β‑thalassaemia intermedia may appear after infancy; α‑thalassaemia trait is often silent. |
| Family history | Consanguinity, affected siblings, parents from malaria‑endemic regions, known carrier status? | Autosomal recessive inheritance; carrier frequency is high in certain Kenyan ethnic groups. |
| Ethnicity / geographic origin | “What is your tribe or region of origin?” | Certain tribes (e.g., Luo, Luhya) have higher carrier rates. |
| Pregnancy / transfusion history | Prior blood transfusions, iron chelation, obstetric complications? | Chronic transfusion leads to iron overload; pregnancy can unmask milder forms. |
| Symptoms of anaemia | Fatigue, dyspnoea on exertion, palpitations, dizziness, pallor, exercise intolerance? | Reduced haemoglobin from ineffective erythropoiesis and haemolysis. |
| Skeletal changes | “Do you have bone pain or facial deformities?” – frontal bossing, maxillary prominence, crew‑cut long bones? | Marrow expansion to compensate for ineffective erythropoiesis causes cortical thinning and facial bone remodeling. |
| Splenomegaly | Abdominal fullness, early satiety, left upper quadrant pain? | Hyperactive spleen sequesters abnormal red cells and destroys them, leading to enlargement. |
| Jaundice / bilirubin | Episodes of yellowing of skin or sclera, especially after infections? | Chronic haemolysis releases unconjugated bilirubin. |
| Growth & development | Delayed height/weight, delayed puberty? | Chronic anaemia and iron overload impair growth hormone axis. |
| Infections | Recurrent fevers, especially after transfusion or splenectomy? | Functional asplenia or splenectomy predisposes to encapsulated organisms; transfusion‑related infections (HIV, hepatitis) are relevant in Kenya. |
| Cardiac symptoms | Palpitations, chest pain, dyspnoea at rest, leg swelling? | Iron deposition in myocardium leads to cardiomyopathy and arrhythmias. |
| Endocrine symptoms | Polyuria, polydipsia, amenorrhea, skin hyperpigmentation? | Iron overload damages pancreas (diabetes), pituitary (hypogonadism), thyroid. |
| Skin changes | “Do you notice dark patches on skin?” – especially over the cheeks? | Hyperpigmentation from hemosiderin deposition. |
Examination
- General – pallor, tachycardia, low BMI, growth retardation – reflect chronic anaemia and nutritional compromise.
- Facial bones – frontal bossing, “chipmunk” facies, maxillary prominence – marrow expansion.
- Skeletal – palpable rib “crew‑cut” deformities, bowing of long bones – cortical thinning from marrow hyperplasia.
- Abdomen – enlarged spleen (often > 10 cm) – splenic sequestration; hepatomegaly from extramedullary haematopoiesis.
- Cardiovascular – high‑output murmur, displaced apex, gallop rhythm – chronic anaemia and early cardiomyopathy.
- Skin – bronze‑brown discoloration, especially over the face and hands – iron overload.
- Neurological – signs of endocrine dysfunction (delayed puberty, hypothyroidism) – iron deposition in pituitary/thyroid.
Differential diagnosis
| Condition | Points toward it | How it differs from thalassaemia |
|---|---|---|
| Iron‑deficiency anaemia | Microcytic hypochromic RBCs, dietary deficiency, heavy menstrual loss | No family history, normal iron studies, no skeletal changes, response to iron therapy |
| Sickle cell disease | Positive sickle cell test, vaso‑occlusive pain crises, African descent | Normocytic or macrocytic, sickled cells on smear, hemoglobin S on electrophoresis, no marrow expansion facial changes |
| Lead poisoning | Occupational exposure, abdominal pain, basophilic stippling | Normal iron studies, elevated blood lead, reversible with chelation, no splenomegaly |
| Autoimmune haemolytic anaemia | Positive Coombs test, warm or cold antibodies, rapid haemolysis | No microcytosis, high reticulocyte count, no family history, no skeletal changes |
| Chronic malaria | Recurrent fevers, positive thick smear, travel history | Episodic anaemia, parasitaemia, responds to antimalarials, no chronic bone changes |
| HIV‑associated anaemia | Positive HIV test, opportunistic infections, ART history | May be normocytic, associated with marrow suppression, not inherited, no facial bone changes |
Investigations
| Test | What it answers | Typical result in thalassaemia |
|---|---|---|
| Full blood count with red cell indices | Microcytosis, hypochromia, RBC count | Low MCV, low MCH, high RBC count (relative) |
| Peripheral smear | Morphology of RBCs | Target cells, basophilic stippling, nucleated RBCs |
| Reticulocyte count | Bone‑marrow response | Elevated retic count (ineffective erythropoiesis) |
| Serum ferritin & transferrin saturation | Iron stores | Markedly raised ferritin (iron overload) |
| Serum iron, TIBC | Distinguish iron‑deficiency vs overload | Normal/high iron, low/normal TIBC |
| Hemoglobin electrophoresis / HPLC | Type and proportion of Hb fractions | ↑ Hb F, ↓ or absent Hb A, ↑ Hb A2 in β‑thalassaemia trait |
| DNA analysis (if available) | Specific gene mutations | β‑globin or α‑globin mutations identified |
| Liver function tests & cardiac MRI (T2*) | Iron overload organ damage | Elevated transaminases, low T2* signal indicating myocardial iron |
| Ultrasound abdomen | Splenomegaly, liver size | Enlarged spleen, possible hepatic iron deposition |
| Endocrine panel (fasting glucose, thyroid, gonadotropins) | Iron‑related endocrine dysfunction | Abnormal glucose, low TSH/T4, low LH/FSH in severe overload |
Diagnosis and severity
- Confirmatory diagnosis – combination of microcytic hypochromic anaemia, characteristic smear, and hemoglobin electrophoresis showing abnormal Hb fractions (↑ Hb F, ↑ Hb A2, ↓/absent Hb A). Molecular testing refines genotype when needed.
- Classification of severity (clinical rather than numeric):
| Category | Criteria | Clinical implications |
|---|---|---|
| Thalassaemia major | Homozygous β‑thalassaemia or 4‑gene α‑thalassaemia (Hb Bart’s); transfusion‑dependent from infancy; Hb < 7 g/dL without transfusion | Requires regular transfusion, aggressive iron chelation, monitoring for cardiac/hepatic iron overload. |
| Thalassaemia intermedia | Compound heterozygotes or milder β‑/α‑genotypes; transfusion‑independent or occasional transfusion; Hb 7–10 g/dL | Intermittent transfusion, chelation if ferritin > 1000 µg/L, surveillance for splenomegaly and bone changes. |
| Thalassaemia trait (carrier) | Heterozygous β‑ or α‑gene deletion; mild microcytosis, normal Hb > 11 g/dL; no clinical anaemia | No treatment needed; counselling for family planning. |
| Severe iron overload | Ferritin > 2500 µg/L or cardiac MRI T2* < 20 ms | Intensify chelation, consider deferasirox or deferoxamine; monitor cardiac function. |
| Complicated disease | Presence of cardiac failure, endocrine failure, hepatic fibrosis, or severe osteoporosis | Multidisciplinary management, possible bone marrow transplant evaluation. |
Severity guides the intensity of transfusion support, chelation strategy, and need for specialist referral (cardiology, endocrinology, hepatology). Regular reassessment every 3–6 months is essential to adjust therapy and prevent irreversible organ damage.
Management
| Phase | Goal | Key Interventions | Monitoring / Safety |
|---|---|---|---|
| Immediate stabilisation | Correct life‑threatening anaemia & hypoxia | • Rapid transfusion of packed red cells (type‑specific, cross‑matched) <br>• Give supplemental O₂ to keep SpO₂ > 94 % <br>• Start IV fluids judiciously (avoid overload) | • Vital signs q15 min → q1 h <br>• Hemoglobin trend (target 8–10 g/dL in children, 10–12 g/dL in adults) <br>• Signs of fluid overload (JVD, crackles) |
| Definitive treatment | Reduce transfusion burden & prevent iron overload | • Regular transfusion programme (maintain target Hb) <br>• Iron chelation (deferoxamine, deferasirox, deferiprone) – choose based on route, adherence, renal/hepatic status <br>• Consider curative options where available: bone‑marrow transplant (matched sibling) or gene‑therapy trials | • Serum ferritin every 3 months; MRI T2* liver & heart annually <br>• Renal & hepatic function (creatinine, ALT/AST) before and during chelation <br>• Audiology & ophthalmology for deferoxamine toxicity |
| Supportive care | Manage complications & improve quality of life | • Folic acid supplementation <br>• Vaccinations (pneumococcal, Hib, hepatitis B, influenza) <br>• Antimicrobial prophylaxis in splenectomised patients (penicillin, pneumococcal vaccine) <br>• Education on recognizing fever, bone pain, and transfusion reactions | • Review growth & development in children <br>• Psychosocial support, counselling on reproductive issues |
| Contra‑indications / safety | Avoid harm | • Deferoxamine contraindicated in severe visual/hearing loss <br>• Deferasirox avoided in severe renal impairment <br>• Bone‑marrow transplant not offered in uncontrolled infection or severe organ damage | • Baseline and periodic ECG for cardiac iron overload <br>• Monitor for chelator‑related cytopenias, GI upset, skin rash |
Complications and prognosis
| Complication | Pathogenesis | Clinical clue | Management |
|---|---|---|---|
| Iron overload | Repeated transfusions → non‑transferrin‑bound iron deposition | Elevated ferritin, hepatic/ cardiac MRI T2* loss | Chelation; consider cardiac transplant if end‑stage |
| Cardiac disease | Iron‑induced cardiomyopathy, arrhythmias | Dyspnoea, tachycardia, cardiomegaly on CXR | Optimize chelation, beta‑blockers for arrhythmias, heart failure therapy |
| Endocrine dysfunction | Iron deposition in pituitary, thyroid, pancreas | Delayed puberty, hypothyroidism, diabetes mellitus | Hormone replacement, insulin, regular endocrine screening |
| Skeletal deformities | Marrow expansion → hair‑on‑end ribs, facial bone changes | Facial bone prominence, frontal bossing | Adequate transfusion to suppress erythropoiesis, physiotherapy |
| Splenomegaly / hypersplenism | Chronic sequestration of abnormal cells | Massive spleen, cytopenias | Consider splenectomy if refractory; vaccinate pre‑op |
| Infections | Functional asplenia, iron‑rich media | Fever, sepsis, especially with encapsulated organisms | Prompt antibiotics, prophylactic penicillin, immunisations |
| Psychosocial impact | Chronic disease burden | School absenteeism, depression | Counselling, support groups |
Prognosis improves markedly with early diagnosis, regular transfusion, and effective chelation. Untreated severe β‑thalassaemia major carries high mortality in the first two decades from cardiac failure or infection. Curative transplant offers > 80 % long‑term survival when performed early.
High‑yield exam points
- Look‑alikes: Iron‑deficiency anaemia (microcytic, low ferritin), sideroblastic anaemia, anemia of chronic disease.
- Common wrong first step: Starting iron supplements in a thalassaemia patient – worsens iron overload.
- Bedside examiner question: “Explain why a patient with β‑thalassaemia major develops frontal bossing.” (Answer: marrow expansion to compensate for ineffective erythropoiesis).
- Key exam finding: “Hair‑on‑end” ribs on chest X‑ray – indicates marrow hyperplasia.
- Management trap: Giving deferoxamine without a proper renal/hepatic assessment – risk of nephro‑/hepatotoxicity.
- Transfusion target: Remember the different Hb targets for children vs adults.
Clinical case
Case: A 12‑year‑old Kenyan girl presents with progressive fatigue, pallor, and a history of receiving blood transfusions every 3 weeks since age 2. She has a markedly enlarged spleen, frontal bossing, and a ferritin of 3 500 µg/L. ECG shows a prolonged QT interval.
Questions
- What is the most appropriate next step in her management?
Answer: Initiate iron chelation therapy (deferasirox preferred for oral administration) after confirming baseline renal and hepatic function.
- Why should iron supplementation be avoided in this patient?
Answer: She already has severe iron overload; additional iron would exacerbate organ toxicity.
- What curative option could be offered if a matched sibling donor is identified?
Answer: Allogeneic hematopoietic stem‑cell transplantation, which can eradicate the disease and stop further transfusion dependence.
Practice questions
Question 1
A 7‑year‑old boy with known β‑thalassaemia major presents with fever, tachycardia, and a new left‑upper‑quadrant pain. His spleen is markedly enlarged. What is the most appropriate immediate action?
A. Start oral iron tablets
B. Give broad‑spectrum IV antibiotics
C. Increase his transfusion interval
D. Order a splenectomy
Answer: B. give broad‑spectrum IV antibiotics
Explanation: Splenic sequestration can precipitate bacterial infection; prompt IV antibiotics are essential before any surgical decision.
Question 2
Which laboratory pattern distinguishes β‑thalassaemia trait from iron‑deficiency anaemia?
A. Low serum ferritin, high TIBC
B. Normal ferritin, high RBC count, target cells
C. Elevated ferritin, low transferrin saturation
D. Macrocytosis with hypersegmented neutrophils
Answer: B. normal ferritin, high RBC count, target cells
Explanation: Thalassaemia trait shows normal iron stores, elevated RBC count and characteristic target cells, unlike iron deficiency.
Question 3
A 20‑year‑old female with β‑thalassaemia intermedia is being considered for deferoxamine therapy. Which finding would be a contraindication to start this chelator?
A. Serum ferritin 2 500 µg/L
B. Mild transaminase elevation
C. Persistent hearing loss
D. Normal renal function
Answer: C. persistent hearing loss
Explanation: Deferoxamine can worsen ototoxicity; alternative chelators are preferred.
Question 4
During a routine visit, a child with thalassaemia major has a ferritin of 1 200 µg/L and an MRI T2* of the heart showing moderate iron loading. Which statement is correct regarding his management?
A. Stop chelation until ferritin falls below 500 µg/L
B. Switch to oral chelator only if cardiac T2* is normal
C. Intensify chelation regimen and repeat cardiac MRI in 12 months
D. Add high‑dose vitamin C to increase iron excretion
Answer: C. intensify chelation regimen and repeat cardiac MRI in 12 months
Explanation: Moderate cardiac iron warrants more aggressive chelation and close monitoring; vitamin C is not recommended due to infection risk.
Question 5
A patient with β‑thalassaemia major is scheduled for bone‑marrow transplant. Which pre‑transplant assessment is essential?
A. Serum vitamin D level
B. Screening for latent TB and HIV
C. Baseline ECG only if symptomatic
D. Routine colonoscopy
Answer: B. screening for latent TB and HIV
Explanation: Immunosuppression post‑transplant can reactivate latent infections; screening is mandatory.
Drafted with AI assistance from standard references and reviewed for structure. Check details against your lecture notes and the Kenya MoH guideline.