Transcript Slide 1

Epidemiology and Disease
Pathophysiology: Thalassaemia
Ali T. Taher, MD
Professor
Department of Internal Medicine
American University of Beirut Medical Center
Beirut, Lebanon
Overview


Definition
Etiology
– Imbalance of globin chain synthesis
– Molecular basis
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Differentiation of thalassaemia major and
thalassaemia intermedia
Epidemiology
Pathophysiology
Diagnosis
– Clinical manifestations
– Complications
– Prognosis

Management of iron overload
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
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
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.
Clinical Forms of β-Thalassaemia
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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.
Thalassaemia Major
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Clinical Features
Clinical manifestations of anaemia emerge at
6 months–2 years
– Infants protected by prenatal HbF production
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Typical presentation includes
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–
–
–
–
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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.
Thalassaemia Major
Molecular Basis
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Patients with β-thalassaemia major have inherited two
β-thalassaemia alleles
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Hypochromic, abnormally shaped red blood cells
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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
–
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Located on each copy of chromosome 11
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.
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.
Molecular Basis of Thalassaemia
Intermedia
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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
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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.
Helpful Clues to Differentiate Major
from Intermedia
Thalassaemia Major
More Likely
Clinical
Presentation (years)
<2
Hb levels (g/dL)
6–7
Liver/spleen enlargement
Severe
Haematologic
HbF (%)
>50
HbA2 (%)
<4
Genetic
Parents
Both carriers of high HbA2
-thalassaemia
Molecular
Type of mutation
Coinheritance of -thalassaemia
Hereditary persistence of
fetal haemoglobin
 -thalassaemia
G XmnI polymorphism
Thalassaemia Intermedia
More Likely
>2
8–10
Moderate to severe
10–50 (may be up to 100%)
>4
1 or both atypical carriers:
- High HbF -thalassaemia
- Borderline HbA2
Severe
No
Mild/silent
Yes
No
No
No
Yes
Yes
Yes
Cappellini N, et al, eds. Thalassaemia International Federation 2000 with permission.
Epidemiology
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Approximately 7% of the world’s population is a
carrier of haemoglobin disorders1
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Between 300,000 and 500,000 infants are born
every year with severe homozygous forms of the
disease1
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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
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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.
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.
β-Thalassaemia Genes, Severity and Ethnic Distribution
Population
Indian
Mediterranean
Black
Mediterranean; African
Japanese
African
Southeast Asian
Black
Mediterranean; Asian Indian
Mediterranean; Asian Indian
Mediterranean
Mediterranean
Chinese
Mediterranean
Mediterranean
Mediterranean
Mediterranean; African American
Southeast Asian
African American
Mediterranean
Mediterranean
Southeast Asian
β-gene Mutation
-619 del
-101
-88
-87
-31
-29
-28
-26
IVS1-nt1
IVS1-nt5
ΙVS1-nt6
IVS1-nt110
IVS2-nt654
IVS2-nt745
codon 39
codon 5
codon 6
codons 41/42
AATAAA to AACAAA
AATAAA to AATGAA
Hb Knossos
HbE
Cappellini N, et al, eds. Thalassaemia International Federation 2000 with permission.
Severity
βο
β++
β++
β++
β++
β++
β++
β++
βο
βο
β+/++
β+
β+
β+
βο
βο
βο
βο
β++
β++
β++
β++
Thalassaemia: Clinical
Manifestations and Treatment
Pathophysiologic Sequelae of Untreated Thalassaemia
and Corresponding Clinical Manifestations
Excess free
-globin chains
Haemolysis
Increased
erythropoietin
synthesis
Reduced tissue
oxygenation
Skeletal
deformities,
osteopaenia
Olivieri NF. N Engl J Med. 1999;341:99.
.
Denaturation
Degradation
Ineffective
erythropoiesis
Membrane
binding of
IgG and C3
Anaemia
Erythroid
marrow
expansion
Formation of haeme
and haemichromes
Iron-mediated
toxicity
Removal of
damaged red cells
Splenomegaly
Increased
Iron absorption
Iron overload
Clinical Manifestations
With permission from Dr. Cappellini.
Clinical Manifestations

Thalassaemia trait has no important clinical
effects
– Activity of the normal β gene on the allelic
chromosome makes enough stable globin
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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.
Complications
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Thalassaemia major complications mostly due to
iron overload and frequent blood transfusions
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–
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Heart failure
Infection (blood transfusion, postsplenectomy)
Hypogonadism and infertility
Diabetes mellitus
Hypothyroidism
Thalassaemia intermedia complications include
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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.
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
90
67
95
83
Cholecystectomy
85
68
15
7
Gallstones
55
63
10
23
EMH
20
24
0
0
Leg ulcers
20
33
0
0
Thrombotic events
28
22
0
0
Cardiopathy*
3
5
10
25
PHT
50†
17
10
11
Abnormal liver enzymes
20
22
55
68
Hepatitis C virus infection 7
33
7
98
Hypogonadism
5
3
80
93
Diabetes mellitus
3
2
12.5
10
Hypothyroidism
3
2
15
11
*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.
Iron Overload
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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)
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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.
Iron Overload
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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
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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
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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.
Iron Overload
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Normal intestinal iron absorption is about 1–
1.5 mg/d
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In thalassaemic patients who do not receive
any transfusion, iron absorption increases
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In individuals who are poorly transfused,
absorption rises to 3–4 mg/d or more
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This represents a supplementary 1–2 g of
iron loading per year
Cappellini N, et al, eds. Thalassaemia International Federation 2000.
Evaluation of Iron Overload
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Serum ferritin concentration
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Noninvasive
Accuracy in iron overload questionable
Liver iron concentration (LIC)
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Liver biopsy
 Reference standard
– SQUID
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Noninvasive, availability limited
– MRI
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Noninvasive, FDA-approved technique
– Others: NTBI and T2*MRI
Olivieri N, Brittenham G. Blood. 1997;89:739.
β-Thalassaemia Major
Treatment
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Conventional treatment/chelation
– The gold standard treatment has been the
administration of blood transfusions and
subsequent iron chelation therapy
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Bone marrow transplantation (BMT)
– BMT has been attempted from donors with
matching alleles
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HbF-inducing therapy
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Gene therapy—the future
Olivieri NF. N Engl J Med. 1999;341:99.
Conclusions
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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
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Iron overload may be present in both
conditions, caused by transfusion therapy or
excess GI iron absorption
Current treatment involves chelation therapy