Epidemiology and Disease Epidemiology and Disease Pathophysiology: Thalassaemia Pathophysiology: Thalassaemia

Ali T. Taher, MDProfessor

Department of Internal Medicine

American University of Beirut Medical Center

Beirut, Lebanon

OverviewOverview DefinitionDefinition EtiologyEtiology

– Imbalance of globin chain synthesisImbalance of globin chain synthesis– Molecular basisMolecular basis

Differentiation of thalassaemia major and thalassaemia Differentiation of thalassaemia major and thalassaemia intermediaintermedia

Epidemiology Epidemiology PathophysiologyPathophysiology DiagnosisDiagnosis

– Clinical manifestationsClinical manifestations– ComplicationsComplications– Prognosis Prognosis

Management of iron overloadManagement of iron overload

DefinitionDefinition The thalassaemias comprise a heterogeneous The thalassaemias comprise a heterogeneous

group of disorders of haemoglobin productiongroup of disorders of haemoglobin production– Normal haemoglobin production partially or completely Normal haemoglobin production partially or completely

suppressed due to defective synthesis of 1 or more suppressed due to defective synthesis of 1 or more components of the globin chainscomponents of the globin chains

Depending on the involved genes, Depending on the involved genes, the defect is classified as the defect is classified as ‑‑thalassaemia thalassaemia or or ‑‑thalassaemiathalassaemia

Under normal conditions, the red cells of the adult Under normal conditions, the red cells of the adult human contain approximately 98% HbA, traces of human contain approximately 98% HbA, traces of HbF, and 2.0% HbA2HbF, and 2.0% HbA2

Cappellini N, et al, eds. Thalassaemia International Federation; 2000.

Clinical Forms of Clinical Forms of ββ-Thalassaemia-Thalassaemia

Thalassaemia major (TM)Thalassaemia major (TM)– Presents in the first year of life Presents in the first year of life

– Subsequently requires regular transfusions and Subsequently requires regular transfusions and iron chelation to surviveiron chelation to survive

Thalassaemia intermedia (TI)Thalassaemia intermedia (TI)– Presents later in life Presents later in life

– May be transfusion independent or require only May be transfusion independent or require only sporadic transfusionssporadic transfusions

Olivieri NF. N Engl J Med. 1999;341:99.

Forget BG. In Hoffman: Hematology: Basic Principles and Practice, 2005.

Thalassaemia MajorThalassaemia MajorClinical FeaturesClinical Features

Clinical manifestations of anaemia emerge at 6 Clinical manifestations of anaemia emerge at 6 months–2 yearsmonths–2 years– Infants protected by prenatal HbF productionInfants protected by prenatal HbF production

Typical presentation includesTypical presentation includes– PallorPallor– IrritabilityIrritability– Growth retardationGrowth retardation– Enlargement of the liver and spleenEnlargement of the liver and spleen– Jaundice Jaundice

If untreatedIf untreated– Facial and skeletal changes result from bone marrow Facial and skeletal changes result from bone marrow

expansionexpansion– Average survival <4 yearsAverage survival <4 years

Forget BG. In Hoffman: Hematology: Basic Principles and Practice, 2005.

Thalassaemia Major Thalassaemia Major Molecular BasisMolecular Basis

Patients with β-thalassaemia major have inherited two β-Patients with β-thalassaemia major have inherited two β-thalassaemia allelesthalassaemia alleles

– Located on each copy of chromosome 11 Located on each copy of chromosome 11

Hypochromic, abnormally shaped red blood cellsHypochromic, abnormally shaped red blood cells

– Contain significantly reduced amounts of haemoglobin than normal Contain significantly reduced amounts of haemoglobin than normal blood cells because of diminished HbA synthesisblood cells because of diminished HbA synthesis

Deposition of precipitated aggregates of free Deposition of precipitated aggregates of free α-globin chains results in accumulationα-globin chains results in accumulation

– Damages erythrocytes, precursor cells in bone marrowDamages erythrocytes, precursor cells in bone marrow

Resulting anaemia so severe that patients usually require Resulting anaemia so severe that patients usually require chronic blood transfusions chronic blood transfusions

TI has an extraordinarily wide clinical spectrum, unlike TM, which presents with severe anaemia requiring frequent blood transfusions

Severe TIPresentation between 2 and 6 yearsRetarded growth and development

Mild TICompletely asymptomatic until adulthood

Cappellini N, et al, eds. Thalassaemia International Federation; 2000.

Thalassaemia IntermediaThalassaemia IntermediaClinical FeaturesClinical Features

Taher A. Blood Cells Mol Dis. 2006;37:12.

Molecular Basis of Thalassaemia Molecular Basis of Thalassaemia IntermediaIntermedia

3 main reasons3 main reasons– Inheritance of a mild (Inheritance of a mild (ββ+) mutation +) mutation

– Presence of a polymorphism for the enzyme Xmn-I Presence of a polymorphism for the enzyme Xmn-I in the Gin the G- promoter region, associated with - promoter region, associated with increased HbFincreased HbF

– Coinheritance of Coinheritance of -thalassaemia-thalassaemia

Increase production of alpha-globin chains byIncrease production of alpha-globin chains by– Triplicated alpha genotype associated to Triplicated alpha genotype associated to

beta-heterozygosity beta-heterozygosity

– Interaction of Interaction of betabeta and and delta delta beta thalassaemiabeta thalassaemia

Cappellini N, et al, eds. Thalassaemia International Federation 2000 with permission.

Helpful Clues to Differentiate Major Helpful Clues to Differentiate Major from Intermediafrom Intermedia

Thalassaemia Major Thalassaemia IntermediaMore 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

EpidemiologyEpidemiology Approximately 7% of the world’s population is a Approximately 7% of the world’s population is a

carrier of haemoglobin disorderscarrier of haemoglobin disorders1 1

Between 300,000 and 500,000 infants are born every Between 300,000 and 500,000 infants are born every year with severe homozygous forms of the diseaseyear with severe homozygous forms of the disease11

An overview of the global distribution of An overview of the global distribution of thalassaemias shows that in addition to the thalassaemias shows that in addition to the Mediterranean countries in which they were first Mediterranean countries in which they were first recognized, thalassaemias are frequently found in recognized, thalassaemias are frequently found in Asia and the Far EastAsia and the Far East22

Population migration has led to spread of this Population migration has led to spread of this condition with its morbidity and mortalitycondition with its morbidity and mortality22

1. Weatherall D, et al. Disease Control Priorities in Developing Countries, 2006.2. Cappellini N, et al, eds. Thalassaemia International Federation; 2000.

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

Thalassaemia—Global DistributionThalassaemia—Global Distribution

Cappellini N, et al, eds. Thalassaemia International Federation 2000, with permission.

Cappellini N, et al, eds. Thalassaemia International Federation 2000 with permission.

β-Thalassaemia Genes, Severity and Ethnic Distributionβ-Thalassaemia Genes, Severity and Ethnic DistributionPopulation β-gene Mutation SeverityIndian -619 del βο

Mediterranean -101 β++

Black -88 β++

Mediterranean; African -87 β++

Japanese -31 β++

African -29 β++

Southeast Asian -28 β++

Black -26 β++

Mediterranean; Asian Indian IVS1-nt1 βο

Mediterranean; Asian Indian IVS1-nt5 βο

Mediterranean ΙVS1-nt6 β+/++

Mediterranean IVS1-nt110 β+

Chinese IVS2-nt654 β+

Mediterranean IVS2-nt745 β+

Mediterranean codon 39 βο

Mediterranean codon 5 βο

Mediterranean; African American codon 6 βο

Southeast Asian codons 41/42 βο

African American AATAAA to AACAAA β++

Mediterranean AATAAA to AATGAA β++

Mediterranean Hb Knossos β++

Southeast Asian HbE β++

Thalassaemia: Clinical Thalassaemia: Clinical Manifestations and TreatmentManifestations and Treatment

.

Pathophysiologic Sequelae of Untreated Thalassaemia Pathophysiologic Sequelae of Untreated Thalassaemia and Corresponding Clinical Manifestationsand Corresponding Clinical Manifestations

HaemolysisIneffective

erythropoiesis

Membranebinding ofIgG and C3

AnaemiaIncreased

erythropoietinsynthesis

Skeletaldeformities,osteopaenia

Erythroidmarrow

expansionIron overload

Splenomegaly

Excess free -globin chains Denaturation

Degradation

Formation of haeme and haemichromes

Iron-mediated toxicity

Removal ofdamaged red cells

Increased

Iron absorption

Reduced tissue

oxygenation

Olivieri NF. N Engl J Med. 1999;341:99.

With permission from Dr. Cappellini.

Clinical ManifestationsClinical Manifestations

Clinical ManifestationsClinical Manifestations

Thalassaemia trait has no important clinical Thalassaemia trait has no important clinical effectseffects– Activity of the normal β gene on the allelic Activity of the normal β gene on the allelic

chromosome makes enough stable globinchromosome makes enough stable globin However, inheritance of 2 defective β-globin However, inheritance of 2 defective β-globin

genes causes a wide spectrum of clinical genes causes a wide spectrum of clinical conditionsconditions

Molecular studies reveal a wide array of Molecular studies reveal a wide array of abnormalities, which underlie above abnormalities, which underlie above phenotypes and help in their identificationphenotypes and help in their identification

Cappellini N, et al, eds. Thalassaemia International Federation; 2000.

ComplicationsComplications Thalassaemia major complications mostly due to iron Thalassaemia major complications mostly due to iron

overload and frequent blood transfusionsoverload and frequent blood transfusions– Heart failureHeart failure

– Infection (blood transfusion, postsplenectomy)Infection (blood transfusion, postsplenectomy)

– Hypogonadism and infertilityHypogonadism and infertility

– Diabetes mellitusDiabetes mellitus

– HypothyroidismHypothyroidism Thalassaemia intermedia complications includeThalassaemia intermedia complications include

– ThrombosisThrombosis

– Pulmonary hypertensionPulmonary hypertension

– Leg ulcersLeg ulcers

– Extramedullary haematopoiesisExtramedullary haematopoiesis

– Endocrine disorders (osteoporosis, hypogonadism)Endocrine disorders (osteoporosis, hypogonadism)

Olivieri NF. N Engl J Med. 1999;341:99.Taher A, et al. Blood Cells Mol Dis. 2006;37:12.

Taher A, et al. Blood Cells Mol Dis. 2006;37:12.

Prevalence of Common Complications in TI vs Prevalence of Common Complications in TI vs TM in Italy and LebanonTM in Italy and Lebanon

Thalassaemia ThalassaemiaComplication (% of TI, Lebanon TI, Italy Major, Lebanon Major, ItalyPatients Affected) (n = 37) (n = 63) (n = 40) (n = 60)Splenectomy 90 67 95 83Cholecystectomy 85 68 15 7Gallstones 55 63 10 23EMH 20 24 0 0Leg ulcers 20 33 0 0Thrombotic events 28 22 0 0Cardiopathy* 3 5 10 25PHT 50† 17 10 11Abnormal liver enzymes 20 22 55 68Hepatitis C virus infection 7 33 7 98Hypogonadism 5 3 80 93Diabetes mellitus 3 2 12.5 10Hypothyroidism 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.

Iron OverloadIron Overload

Iron overload occurs when iron intake is Iron overload occurs when iron intake is increased over a sustained period of timeincreased over a sustained period of time– Transfusion of red blood cells (thalassaemia Transfusion of red blood cells (thalassaemia

major)major)

– Increased absorption of iron from the digestive Increased absorption of iron from the digestive tract (thalassaemia intermedia)tract (thalassaemia intermedia)

Because there is no mechanism in humans to Because there is no mechanism in humans to excrete the excess iron, this has to be excrete the excess iron, this has to be removed by chelation therapyremoved by chelation therapy

Forget BG. In Hoffman: Hematology: Basic Principles and Practice, 2005.

Iron Overload Iron Overload

1 unit of blood contains approximately 1 unit of blood contains approximately 200–250 mg of iron200–250 mg of iron1 1

– Chronic transfusion-dependent patients have an Chronic transfusion-dependent patients have an iron excess of ~ 0.32–0.64 mg/kg/diron excess of ~ 0.32–0.64 mg/kg/d22

With repeated infusions, iron accumulatesWith repeated infusions, iron accumulates– Signs of iron overload can be seen after Signs of iron overload can be seen after

anywhere from 10 to 20 transfusions, such as in anywhere from 10 to 20 transfusions, such as in thalassaemia major patientsthalassaemia major patients22

Iron overload can lead to early mortalityIron overload can lead to early mortality22

1. Andrews NC. N Engl J Med. 1999;341:1986. 2. Porter JB. B J Haematol. 2001;115:239.

Iron OverloadIron Overload

Normal intestinal iron absorption is about 1Normal intestinal iron absorption is about 1––1.5 mg/d1.5 mg/d

In thalassaemic patients who do not receive In thalassaemic patients who do not receive any transfusion,any transfusion, ironiron absorption increasesabsorption increases

In individuals who are poorly transfused, In individuals who are poorly transfused, absorption rises to 3absorption rises to 3––4 mg/d or more4 mg/d or more

This represents a supplementary 1This represents a supplementary 1––2 g of iron 2 g of iron loading per yearloading per year

Cappellini N, et al, eds. Thalassaemia International Federation 2000.

Evaluation of Iron OverloadEvaluation of Iron Overload

Serum ferritin concentrationSerum ferritin concentration– NoninvasiveNoninvasive– Accuracy in iron overload questionableAccuracy in iron overload questionable

Liver iron concentration (LIC)Liver iron concentration (LIC)– Liver biopsyLiver biopsy

Reference standardReference standard

– SQUIDSQUID Noninvasive, availability limitedNoninvasive, availability limited

– MRIMRI Noninvasive, FDA-approved techniqueNoninvasive, FDA-approved technique

– Others: NTBI and T2*MRIOthers: NTBI and T2*MRI

Olivieri N, Brittenham G. Blood. 1997;89:739.

ββ--Thalassaemia MajorThalassaemia Major TreatmentTreatment

Conventional treatment/cheConventional treatment/chelationlation– The gold standard treatment has been the The gold standard treatment has been the

administration of blood transfusions and administration of blood transfusions and subsequent iron chelation therapysubsequent iron chelation therapy

Bone marrow transplantation (BMT)Bone marrow transplantation (BMT)– BMT has been attemptedBMT has been attempted from donors with from donors with

matching allelesmatching alleles

HbF-inducing therapyHbF-inducing therapy Gene therapyGene therapy—the future—the future

Olivieri NF. N Engl J Med. 1999;341:99.

ConclusionsConclusions

Thalassaemias heterogeneous group of Thalassaemias heterogeneous group of disorders of haemoglobin productiondisorders of haemoglobin production– ββ--TM present in first year of life, requires TM present in first year of life, requires

transfusionstransfusions– ββ-TI later presentation, may not require -TI later presentation, may not require

transfusion therapytransfusion therapy Iron overload may be present in both Iron overload may be present in both

conditions, caused by transfusion therapy or conditions, caused by transfusion therapy or excess GI iron absorptionexcess GI iron absorption

Current treatment involves chelation therapyCurrent treatment involves chelation therapy