🩸 Thalassemia (Including Iron Overload)

1. Definition

Thalassemia is a group of inherited autosomal recessive blood disorders caused by reduced or absent synthesis of alpha or beta globin chains, leading to chronic hemolytic anemia.
Severe forms require lifelong blood transfusions, which can result in iron overload and multi-organ complications.

2. Causes

Genetic mutations in the genes encoding:
- Alpha-globin chains (HBA1, HBA2)
- Beta-globin chains (HBB gene)
Causes imbalance in globin chain production, leading to ineffective erythropoiesis and hemolysis

3. Risk Factors

Family history of thalassemia
Consanguineous marriages
High prevalence in Mediterranean, Middle East, Indian, Chinese, and Southeast Asian populations
Carrier parents (both father and mother with trait)

4. Types

Type	Description
Alpha Thalassemia	Deletion of 1–4 alpha genes
- Silent Carrier	1 gene deleted, asymptomatic
- Alpha Trait	2 genes deleted, mild anemia
- HbH Disease	3 genes deleted, moderate hemolytic anemia
- Hydrops Fetalis	4 gene deletion, usually fatal in utero
Beta Thalassemia	Mutation in beta-globin gene
- Beta Thalassemia Minor	One mutated gene (carrier), mild anemia
- Beta Thalassemia Intermedia	Moderate anemia, variable transfusion needs
- Beta Thalassemia Major	Both genes affected, severe anemia, transfusion dependent

5. Pathogenesis

Imbalance of globin chains leads to:
- Ineffective erythropoiesis (destruction of immature RBCs in bone marrow)
- Peripheral hemolysis (shortened RBC lifespan)
Leads to:
- Anemia
- Bone marrow expansion
- Iron overload due to:
  - Increased absorption from gut (even without transfusion)
  - Chronic blood transfusions

6. Clinical Presentation

Symptoms

Pallor, fatigue
Poor growth
Abdominal distension (hepatosplenomegaly)
Bone pain or deformities
Dark urine

Signs

Severe anemia (pale skin, tachycardia)
Jaundice (from hemolysis)
Frontal bossing, maxillary prominence (marrow expansion)
Hepatosplenomegaly
Growth retardation
Pubertal delay (due to iron overload)

7. Organ & System Complications

System	Complication
Cardiac	Cardiomyopathy, arrhythmia (iron deposition)
Endocrine	Diabetes, hypothyroidism, hypogonadism
Liver	Fibrosis, cirrhosis, hepatitis B/C from transfusions
Bone	Osteopenia, fractures, marrow expansion
Growth & Puberty	Short stature, delayed puberty
Infection	Risk from splenectomy, transfusion-transmitted diseases
Gallbladder	Pigmented gallstones from chronic hemolysis

8. Diagnostic Investigations

Test	Purpose
CBC	Microcytic hypochromic anemia
Peripheral blood film	Target cells, nucleated RBCs
Reticulocyte count	May be elevated due to hemolysis
Hb electrophoresis	Identify HbA, HbF, HbA2 proportions
DNA analysis	Confirm alpha or beta thalassemia mutations

9. Other Relevant Investigations

Test	Purpose
Serum ferritin	Monitor iron overload
Liver MRI T2	Quantify liver iron stores
Cardiac MRI T2	Detect cardiac iron overload
LFT	Liver function monitoring
Viral markers (HBV, HCV, HIV)	Screen before transfusions
Bone age, hormone profile	Growth and puberty assessment
Echocardiogram	Cardiac function

10. Treatment

Curative/Definitive

Allogeneic bone marrow transplant (BMT) – only curative option

Empirical

Regular blood transfusions (every 2–5 weeks for beta major)
Folic acid supplementation

Supportive

Iron chelation therapy to manage iron overload:
- Deferoxamine (SC/IV)
- Deferiprone (oral)
- Deferasirox (oral)
Splenectomy if hypersplenism or excessive transfusion needs
Vaccinations: Pneumococcus, meningococcus, H. influenzae (especially post-splenectomy)
Endocrine and growth hormone therapy as needed

Palliative

Pain management (bone/joint pain)
Psychological and family support

11. Long-term Treatment Side Effects

Side Effects of Iron Chelators

Medication	Side Effects	Monitoring Tests	Expected Results
Deferoxamine (SC/IV)	Ototoxicity, visual disturbances, local injection site pain	Audiometry, eye exams	Normal hearing and vision
Deferasirox (oral)	Renal toxicity, hepatic dysfunction, GI upset	Serum creatinine, ALT, bilirubin	Stable renal and liver function
Deferiprone (oral)	Agranulocytosis, GI symptoms, arthralgia	CBC weekly (initially), LFTs	Normal WBC count, stable LFTs

Complications of Iron Overload

Multiple blood transfusion leads to iron overload
It also leads to endocrine failure predisposing to DM, hypogonadism and hypothyroidism

Complication	Monitoring Tests	Expected Results
Liver: fibrosis and cirrhosis	Serum ferritin (every 3–6 months), MRI T2* liver, LFTs	Ferritin < 1000 ng/mL, normal liver iron, stable LFTs
Cardiac: Cardiomyopathy and arrhythmias	MRI T2* heart, echocardiogram, ECG	Normal cardiac iron, preserved ejection fraction
Diabetes	Fasting glucose, HbA1c, OGTT	Normal glucose and HbA1c
Hypogonadism	FSH, LH, testosterone/estradiol, growth and puberty assessments	Normal hormone levels for age
Hypothyroidism	TSH, free T4	TSH and T4 within normal range
Transfusion-transmitted infections (HBV, HCV, HIV)	Viral serologies: HBsAg, anti-HCV, anti-HIV	Negative viral markers

12. Surveillance for the Disease

Domain	Frequency	What to Monitor
CBC & Hb level	Before each transfusion	Maintain pre-transfusion Hb ~9–10 g/dL
Iron overload	Every 3–6 months	Ferritin, MRI T2* of liver and heart
Liver function	Every 6–12 months	ALT, AST, bilirubin
Cardiac	Annually	Echo, cardiac MRI (if iron overload suspected)
Endocrine	Annually	Glucose, thyroid, sex hormones, bone profile
Growth/puberty	Every visit	Height, weight, Tanner staging
Hearing/vision	Yearly (if on deferoxamine)	Audiometry, ophthalmology
Bone health	1–2 yearly	DEXA scan, calcium, vitamin D

13. Malaysia Support Group for Parents

Support Group	Description	Contact/Link
Malaysia Thalassaemia Association (MTA)	National patient support & advocacy group	Facebook: MTA
Persatuan Thalassaemia Malaysia	Local community chapters and events	Often affiliated with hospital clinics
Hospital-based clinics (HKL, Penang GH, HUSM, Sabah GH)	Offer transfusion, chelation, genetic counseling	Request referral from pediatric hematology