1. Epidemiology and Disease Pathophysiology: Thalassaemia
Ali T. Taher, MD
Professor
Department of Internal Medicine
American University of Beirut Medical Center
Beirut, Lebanon

2. Overview Definition Etiology
Imbalance of globin chain synthesis
Molecular basis
Differentiation of thalassaemia major and thalassaemia intermedia
Epidemiology
Pathophysiology
Diagnosis
Clinical manifestations
Complications
Prognosis
Management of iron overload

3. Definition
The thalassaemias comprise a heterogeneous group of disorders of haemoglobin production
Normal haemoglobin production partially or completely suppressed due to defective synthesis of 1 or more components of the globin chains
Depending on the involved genes, the defect is classified as ‑thalassaemia or ‑thalassaemia
Under normal conditions, the red cells of the adult human contain approximately 98% HbA, traces of HbF, and 2.0% HbA2
Cappellini N, et al, eds. Thalassaemia International Federation; 2000.

4. Clinical Forms of β-Thalassaemia
Thalassaemia major (TM)
Presents in the first year of life
Subsequently requires regular transfusions and iron chelation to survive
Thalassaemia intermedia (TI)
Presents later in life
May be transfusion independent or require only sporadic transfusions
Olivieri NF. N Engl J Med. 1999;341:99.

5. Thalassaemia Major Clinical Features
Clinical manifestations of anaemia emerge at 6 months–2 years
Infants protected by prenatal HbF production
Typical presentation includes
Pallor
Irritability
Growth retardation
Enlargement of the liver and spleen
Jaundice
If untreated
Facial and skeletal changes result from bone marrow expansion
Average survival <4 years
Forget BG. In Hoffman: Hematology: Basic Principles and Practice, 2005.

6. Thalassaemia Major Molecular Basis
Patients with β-thalassaemia major have inherited two β-thalassaemia alleles
Located on each copy of chromosome 11
Hypochromic, abnormally shaped red blood cells
Contain significantly reduced amounts of haemoglobin than normal blood cells because of diminished HbA synthesis
Deposition of precipitated aggregates of free α-globin chains results in accumulation
Damages erythrocytes, precursor cells in bone marrow
Resulting anaemia so severe that patients usually require chronic blood transfusions
Forget BG. In Hoffman: Hematology: Basic Principles and Practice, 2005.

7. Thalassaemia Intermedia Clinical Features
TI has an extraordinarily wide clinical spectrum, unlike TM, which presents with severe anaemia requiring frequent blood transfusions
Mild TI
Completely asymptomatic
until adulthood
Severe TI
Presentation between 2 and 6 years
Retarded growth and development
Cappellini N, et al, eds. Thalassaemia International Federation; 2000.

8. Molecular Basis of Thalassaemia Intermedia
3 main reasons
Inheritance of a mild (β+) mutation
Presence of a polymorphism for the enzyme Xmn-I in the G- promoter region, associated with increased HbF
Coinheritance of -thalassaemia
Increase production of alpha-globin chains by
Triplicated alpha genotype associated to beta-heterozygosity
Interaction of beta and delta beta thalassaemia
Taher A. Blood Cells Mol Dis. 2006;37:12.

9. Helpful Clues to Differentiate Major from Intermedia
Thalassaemia Major Thalassaemia Intermedia More Likely More Likely
Clinical Presentation (years) <2 >2 Hb levels (g/dL) 6–7 8–10 Liver/spleen enlargement Severe Moderate to severe
Haematologic HbF (%) >50 10–50 (may be up to 100%) HbA2 (%) <4 >4
Genetic Parents Both carriers of high HbA2 1 or both atypical carriers: -thalassaemia - High HbF -thalassaemia - Borderline HbA2
Molecular Type of mutation Severe Mild/silent Coinheritance of -thalassaemia No Yes Hereditary persistence of fetal haemoglobin No Yes  -thalassaemia No Yes G XmnI polymorphism No Yes
Cappellini N, et al, eds. Thalassaemia International Federation 2000 with permission.

10. Epidemiology
Approximately 7% of the world’s population is a carrier of haemoglobin disorders1
Between 300,000 and 500,000 infants are born every year with severe homozygous forms of the disease1
An overview of the global distribution of thalassaemias shows that in addition to the Mediterranean countries in which they were first recognized, thalassaemias are frequently found in Asia and the Far East2
Population migration has led to spread of this condition with its morbidity and mortality2
1. Weatherall D, et al. Disease Control Priorities in Developing Countries, 2006.
2. Cappellini N, et al, eds. Thalassaemia International Federation; 2000.

11. Thalassaemia—Global Distribution
Due to the continual migration of populations from one area to another, there is virtually no country of the world now in which thalassaemia does not affect some percentage of the inhabitants
Cappellini N, et al, eds. Thalassaemia International Federation 2000, with permission.

12. β-Thalassaemia Genes, Severity and Ethnic Distribution
Population
β-gene Mutation
Severity
Indian
-619 del βο
Mediterranean
-101
β++
Black
-88
Mediterranean; African
-87
Japanese
-31
African
-29
Southeast Asian
-28
-26
Mediterranean; Asian Indian
IVS1-nt1
IVS1-nt5
ΙVS1-nt6
β+/++
IVS1-nt110 β+
Chinese
IVS2-nt654
IVS2-nt745
codon 39
codon 5
Mediterranean; African American
codon 6
codons 41/42
African American
AATAAA to AACAAA
AATAAA to AATGAA
Hb Knossos
HbE
Cappellini N, et al, eds. Thalassaemia International Federation 2000 with permission.

13. Thalassaemia: Clinical Manifestations and Treatment

14. Pathophysiologic Sequelae of Untreated Thalassaemia and Corresponding Clinical Manifestations
Excess free -globin chains
Formation of haeme and haemichromes
Denaturation Degradation
Iron-mediated toxicity
Haemolysis
Ineffective erythropoiesis
Membrane binding of IgG and C3
Removal of damaged red cells
Increased erythropoietin synthesis
Anaemia
Splenomegaly
{Olivieri 1999;Fig 3, p102}
Reduced tissue oxygenation
Skeletal deformities, osteopaenia
Erythroid marrow expansion
Increased Iron absorption
Iron overload
Olivieri NF. N Engl J Med. 1999;341:99. .

15. Clinical Manifestations
With permission from Dr. Cappellini.

16. Clinical Manifestations
Thalassaemia trait has no important clinical effects
Activity of the normal β gene on the allelic chromosome makes enough stable globin
However, inheritance of 2 defective β-globin genes causes a wide spectrum of clinical conditions
Molecular studies reveal a wide array of abnormalities, which underlie above phenotypes and help in their identification
Cappellini N, et al, eds. Thalassaemia International Federation; 2000.

17. Complications
Thalassaemia major complications mostly due to iron overload and frequent blood transfusions
Heart failure
Infection (blood transfusion, postsplenectomy)
Hypogonadism and infertility
Diabetes mellitus
Hypothyroidism
Thalassaemia intermedia complications include
Thrombosis
Pulmonary hypertension
Leg ulcers
Extramedullary haematopoiesis
Endocrine disorders (osteoporosis, hypogonadism)
Olivieri NF. N Engl J Med. 1999;341:99.
Taher A, et al. Blood Cells Mol Dis. 2006;37:12.

18. Prevalence of Common Complications in TI vs TM in Italy and Lebanon
Thalassaemia Thalassaemia Complication (% of TI, Lebanon TI, Italy Major, Lebanon Major, Italy Patients Affected) (n = 37) (n = 63) (n = 40) (n = 60)
Splenectomy
Cholecystectomy
Gallstones
EMH
Leg ulcers
Thrombotic events
Cardiopathy*
PHT 50†
Abnormal liver enzymes
Hepatitis C virus infection
Hypogonadism
Diabetes mellitus
Hypothyroidism
*Fractional shortening <35%.
†PHT was defined as pulmonary artery systolic pressure >30 mmHg. A well enveloped tricuspid regurgitant jet velocity could be detected in only 20 patients, so frequency was assessed in these patients only.
Taher A, et al. Blood Cells Mol Dis. 2006;37:12.

19. Iron Overload
Iron overload occurs when iron intake is increased over a sustained period of time
Transfusion of red blood cells (thalassaemia major)
Increased absorption of iron from the digestive tract (thalassaemia intermedia)
Because there is no mechanism in humans to excrete the excess iron, this has to be removed by chelation therapy
Forget BG. In Hoffman: Hematology: Basic Principles and Practice, 2005.

20. Iron Overload
1 unit of blood contains approximately 200–250 mg of iron1
Chronic transfusion-dependent patients have an iron excess of ~ 0.32–0.64 mg/kg/d2
With repeated infusions, iron accumulates
Signs of iron overload can be seen after anywhere from 10 to 20 transfusions, such as in thalassaemia major patients2
Iron overload can lead to early mortality2
1. Andrews NC. N Engl J Med. 1999;341:1986.
2. Porter JB. B J Haematol. 2001;115:239.

21. Iron Overload Normal intestinal iron absorption is about 1–1.5 mg/d
In thalassaemic patients who do not receive any transfusion, iron absorption increases
In individuals who are poorly transfused, absorption rises to 3–4 mg/d or more
This represents a supplementary 1–2 g of iron loading per year
Cappellini N, et al, eds. Thalassaemia International Federation 2000.

22. Evaluation of Iron Overload
Serum ferritin concentration
Noninvasive
Accuracy in iron overload questionable
Liver iron concentration (LIC)
Liver biopsy
Reference standard
SQUID
Noninvasive, availability limited
MRI
Noninvasive, FDA-approved technique
Others: NTBI and T2*MRI
Olivieri N, Brittenham G. Blood. 1997;89:739.

23. β-Thalassaemia Major Treatment
Conventional treatment/chelation
The gold standard treatment has been the administration of blood transfusions and subsequent iron chelation therapy
Bone marrow transplantation (BMT)
BMT has been attempted from donors with matching alleles
HbF-inducing therapy
Gene therapy—the future
Olivieri NF. N Engl J Med. 1999;341:99.

24. Conclusions
Thalassaemias heterogeneous group of disorders of haemoglobin production
β-TM present in first year of life, requires transfusions
β-TI later presentation, may not require transfusion therapy
Iron overload may be present in both conditions, caused by transfusion therapy or excess GI iron absorption
Current treatment involves chelation therapy