Physiology
- Hemoglobin A
- Major adult hemoglobin
- Tetramer composed of one pair of alpha globin chains and one pair of beta globin chains
- Globin chain synthesis is normally tightly regulated: ratio of alpha/non-alpha chains is 1.00 ± 0.05
- Alpha globin chains are very insoluble
- Beta globin chains are soluble -> they can assemble to form homotetrameric HbH
- Normal Hemoglobin Electrophoresis
- HbA: 95-98%
- HbS: 0%
- HbC: 0%
- HbF: <1%
- HbA2: 2.5%
- Thalassemias: spectrum of diseases where there is decreased or absent production of one or more of the globin chains, resulting in an alteration in the normal alpha/non-alpha chain ratio
Alpha Thalassemia Minima (Silent Carrier of Alpha Thalassemia)
Physiology
- Loss of One of the Four Alpha Globin Genes
- Heterozygous for alpha(+) thalassemia -> aa/a-
Diagnosis
- Complete Blood Count (CBC) (see Complete Blood Count, [[Complete Blood Count]] and Peripheral Smear (see Peripheral Blood Smear, [[Peripheral Blood Smear]])
- Absence of Anemia
- Absent-Slight Microcytosis
- Slight Hypochromia (see Peripheral Blood Smear, [[Peripheral Blood Smear]]): might be noted
- Hemoglobin Electrophoresis: normal
- DNA Analysis: only reliable diagnostic method
Clinical Manifestations
General Comments
Hematologic Manifestations
- Risk of Offspring with HbH Disease: can occur with individual who carries this allele and mates with a partner carrying the alpha thalassemia-1 allele
Alpha Thalassemia Minor
Physiology
- Loss of Two of the Four Alpha Globin Genes
- Heterozygous for Alpha Thalassemia-1 Trait (Heterozygous for Alpha (0) Thalassemia): both alpha genes on one chromsome have been deleted -> aa/– (“cis” deletion)
- This genetic type occurs more commonly in Asians
- Homozygous for Alpha Thalassemia-2 Trait (Homozygous for Alpha (+) Thalassemia): one alpha gene has been deleted from each chromsome -> a-/a- (“trans” deletion)
- This is the most common genetic type in patients of African origin (“cis” deletion is rare in this population): usually involves the less active alpha globin allele (leading to milder disease than that seen in Asian populations, where “cis” deletion is more common)
Diagnosis
- Complete Blood Count (CBC) (see Complete Blood Count, [[Complete Blood Count]] and Peripheral Smear (see Peripheral Blood Smear, [[Peripheral Blood Smear]])
- Hemoglobin Electrophoresis: normal
- Absence of Elevation of HbA2 (in contrast to beta thalassemia)
- Slight Elevation of HbF
- 3-8% Hb Barts at Birth
Clinical Manifestations
General Comments
- Clinically resembles mild beta thalassemia trait
Hematologic Manifestations
- Mild Microcytic Anemia (see Anemia, [[Anemia]])
Deletional Form of Hemoglobin H Disease (Alpha Thalassemia Intermedia)
Physiology
- Loss of Three of the Four Alpha Globin Genes
- Compound Heterozygosity for Both the Alpha Thalassemia-2 Trait and the Alpha Thalassemia-1 Trait -> a-/–
Diagnosis
- Complete Blood Count (CBC) (see Complete Blood Count, [[Complete Blood Count]] and Peripheral Smear (see Peripheral Blood Smear, [[Peripheral Blood Smear]])
- Hemoglobin Electrophoresis
- 20-40% Hb Barts at Birth
- 5-30% HbH in Adults
Clinical Manifestations
General Comments
- Less severe than non-deletional HbH disease
Hematologic Manifestations
- Dramatically Left-Shifted Oxygen Dissociation Curve: due to HbH being a poorly functional oxygen carrier
- Moderate Microcytic/Hemolytic Anemia (see Anemia, [[Anemia]])
- Hemolytic Anemia Throughout Gestation
- Neonatal Jaundice
- Hydrops Fetalis: may occur
Non-Deletional Form of Hemoglobin H Disease (Alpha Thalassemia Intermedia)
Physiology
- Loss of Two of the Four Alpha Globin Genes + Alpha Chain Mutation in One the Remaining Genes
- Compound Heterozygosity for Both the Alpha Thalassemia-1 Trait and Hemoglobin Constant Spring
Diagnosis
Clinical Manifestations
General Comments
- More severe than deletional HbH disease
Hematologic Manifestations
- Dramatically Left-Shifted Oxygen Dissociation Curve: due to HbH being a poorly functional oxygen carrier
- Microcytic/Hemolytic Anemia (see Anemia, [[Anemia]])
- Hemolytic Anemia Throughout Gestation
- Neonatal Jaundice
- Hydrops Fetalis: may occur
Acquired Hemoglobin H Disease (Acquired Alpha Thalassemia, Alpha Thalassemia Myelodysplastic Syndrome)
Etiology
- Myelodysplastic Syndrome (MDS) (see Myelodysplastic Syndrome, [[Myelodysplastic Syndrome]]): occurs in 8% of MDS cases
- Other Myeloproliferative Disorders: occurs in 2.5% of cases
Physiology
- Acquired Somatic Mutation of ATRX: ATRX is an X-linked gene encoding a chromatin-associated protein
- Acquired Deletions of Alpha Globin Loci
Diagnosis
Clinical Manifestations
- Microcytic Anemia (see Anemia, [[Anemia]])
Hydrops Fetalis with Hb Barts
Physiology
- Loss of All Four Alpha Globin Genes
- Homozygosity for the Alpha Thalassemia-1 Trait -> –/–
Diagnosis
- Complete Blood Count (CBC) (see Complete Blood Count, [[Complete Blood Count]] and Peripheral Smear (see Peripheral Blood Smear, [[Peripheral Blood Smear]])
- Microcytic Anemia (see Anemia, [[Anemia]])
- Hemoglobin Electrophoresis
- Hb Barts Present
- Hb Portland Present
- HbH Present
- Absent HbA/HbF/HbA2
Clinical Manifestations
- Fatal Microcytic Anemia (see Anemia, [[Anemia]])
Beta Thalassemia Minor (Beta Thalassemia Trait)
Epidemiology
Highest Population Risk Groups
- General Comments: likely related to selective pressure from Plasmodium Falciparum malaria (over which the beta thalassemia trait is believed to offer some survival advantage)
- Africa
- Central Asia
- Far East/Southeast Asia
- Indian Subcontinent
- Mediterranean
- Cyprus: prevalence is 14%
- Sardinia: prevalence is 12%
- Middle East
- Transcaucasus
- Armenia
- Georgia
- Azerbaijan
Physiology
- Genetics: Heterozygous State with One Normal Beta Globin Allele and One Beta Globin Thalassemic Allele (Tt)
Diagnosis
- Complete Blood Count (CBC) (see Complete Blood Count, [[Complete Blood Count]] and Peripheral Smear (see Peripheral Blood Smear, [[Peripheral Blood Smear]])
- Mild Microcytic Anemia (see Anemia, [[Anemia]]): Hct usually >30%
- Mean Corpuscular Volume (MCV) Usually <75 fL: microcytosis is usually more severe (and anemia less severe) than that observed in iron deficiency anemia
- In contrast, in iron deficiency anemia: MCV doesn’t fall <80 fL until Hct decreases to <30%
- Hypochromia (see Peripheral Blood Smear, [[Peripheral Blood Smear]])
- Increased Total RBC Count: often in the polycythemic range
- Normal Red Cell Distribution Width (RDW): since nearly all cells are microcytic and hypochromic
- In contrast, in iron deficiency anemia: RDW is increased
- Target Cells (see Peripheral Blood Smear, [[Peripheral Blood Smear]]): more dramatic than that seen in all but the most severe cases of iron deficiency anemia
- Teardrop Cells (Dacrocytes) (see Peripheral Blood Smear, [[Peripheral Blood Smear]]: not seen in iron deficiency anemia
- Hemoglobin Electrophoresis
- HbA: accounts for >90 percent of the hemoglobin
- HbA2: elevated (usually 3.5-78%) -> however, a normal HbA2 does not rule out beta thalassemia (due to some cases with delta-beta or gamma-delta-beta thalassemia trait or when the beta thalassemia trait is co-inherited with a delta globin gene mutation)
- HbF: increased in 50% of patients
Clinical Manifestations
General Comments
Cardiovascular Manifestations
- Protection Against Arterial Thromboembolic Events: studies indicate that beta thalassemia trait confers a protective effect against arterial cardiovascular and cerebrovascular disease in male patients
- Likely due to low serum cholesterol, slight anemia, microcytosis, and a decrease in blood viscosity
Hematologic Manifestations
- Mild Microcytic Anemia (see Anemia, [[Anemia]])
- Splenomegaly (see Splenomegaly, [[Splenomegaly]])
- Diagnosis: splenic volume (by ultrasound) is 29-67% greater in those with beta thalassemia minor as compared to controls
- Clinical: however, the spleen is palpable in <20% of patients
Beta Thalassemia Intermedia
Epidemiology
Highest Population Risk Groups
- General Comments: likely related to selective pressure from Plasmodium Falciparum malaria (over which the beta thalassemia trait is believed to offer some survival advantage)
- Africa
- Central Asia
- Far East/Southeast Asia
- Indian Subcontinent
- Mediterranean
- Cyprus: prevalence is 14%
- Sardinia: prevalence is 12%
- Middle East
- Transcaucasus
- Armenia
- Georgia
- Azerbaijan
Physiology
- Genetics: Compound Heterozygote of Two Thalassemia Variants
Diagnosis
- Complete Blood Count (CBC) (see Complete Blood Count, [[Complete Blood Count]] and Peripheral Smear (see Peripheral Blood Smear, [[Peripheral Blood Smear]])
- Hemoglobin Electrophoresis
- HbA2: elevated (usually 3.5-78%) -> however, a normal HbA2 does not rule out beta thalassemia (due to some cases with delta-beta or gamma-delta-beta thalassemia trait or when the beta thalassemia trait is co-inherited with a delta globin gene mutation)
- HbF: increased in 50% of patients
Clinical Manifestations
General Comments
- Definition: defined as patient with symptomatic beta thalassemia who does not require transfusion during at least the first few years of life
- These patients are generally able to survive into the second decade of life without chronic hypertransfusion therapy (ie: they have non-transfusion-dependent thalassemia)
- Variability of Clinical Manifestations: considerable variability in clinical manifestations
Gastrointestinal/Hepatic Manifestations
- Hepatomegaly (see Hepatomegaly, [[Hepatomegaly]]): due to increased RBC destruction and hepatic extramedullary hematopoiesis
Hematologic Manifestations
- Microcytic Anemia (see Anemia, [[Anemia]])
- Splenomegaly (see Splenomegaly, [[Splenomegaly]]): due to increased red cell destruction and splenic extramedullary hematopoiesis
Rheumatologic/Orthopedic Manifestations
- Bony Abnormalities
- “Chipmunk Facies”
- Frontal Bossing
- Delayed Skeletal Maturation
- Osteoporosis (see Osteoporosis, [[Osteoporosis]])
Treatment
Packed Red Blood Cell (PRBC) Hypertransfusion (see Packed Red Blood Cells, [[Packed Red Blood Cells]])
- Usually only require transfusion when red blood cell production is impaired due to an acute event which impairs eryhthropoiesis (such as infection, etc)
Beta Thalassemia Major
Epidemiology
Highest Population Risk Groups
- General Comments: likely related to selective pressure from Plasmodium Falciparum malaria (over which the beta thalassemia trait is believed to offer some survival advantage)
- Africa
- Central Asia
- Far East/Southeast Asia
- Indian Subcontinent
- Mediterranean
- Cyprus: prevalence is 14%
- Sardinia: prevalence is 12%
- Middle East
- Transcaucasus
- Armenia
- Georgia
- Azerbaijan
Physiology
Genetics
- Inheritance of Recessive Thalassemia Trait from Both Parents
- Beta Globin Gene is a Single Copy on Chromosome 11: inheritance follows Mendelian genetics
- Parents Would Both Be Tt: where T = normal allele, t = thalassemia trait
- Therefore, probability of these parents giving birth to homozygous child (tt) with beta thalassemia major would be 25%
- Although both parents would be expected to be phenotypically “normal”, they would have normal-near normal hemoglobin levels with low MCV (usually 60-70’s)
Absent or Significantly Impaired Beta Globin Chain Synthesis with Presence of Excess Alpha Globin Chains
- Excess Alpha Globin Chains are Unstable and Precipitate Within the Cell: results in increased synthesis of reactive oxygen species -> erythroid membrane damage -> ineffective erythropoiesis and hemolysis -> iron overload
- Degree of Alpha Globin Chain Excess Determines the Severity of Clinical Manifestations
- Note: the major non-alpha globin produced at the time of birth is gamma globin -> therefore, the major hemoglobin synthesized in early postnatal life is fetal hemoglobin (it is not until fetal hemoglobin production wanes, in the second 6 months of life, that the symptoms of beta thalassemia occur)
Diagnosis
- Complete Blood Count (CBC) (see Complete Blood Count, [[Complete Blood Count]] and Peripheral Smear (see Peripheral Blood Smear, [[Peripheral Blood Smear]])
- Hemoglobin Electrophoresis
- Hemoglobin A: absent-severely decreased (although variable amounts may be present from transfusions)
- Hemoglobin F: present
- Hemoglobin A2: present
- Hyperbilirubinemia (see Hyperbilirubinemia, [[Hyperbilirubinemia]]): due to severe hemolytic anemia
- Often with other elevated liver function tests (LFT’s)
- Hyperferritinemia (see Hyperferritinemia, [[Hyperferritinemia]]): due to iron overload
- Hypergammaglobulinemia
Clinical Manifestations
General Comments
- Timing of Disease Onset
- Infants are Normal at Birth: as beta globin synthesis is not essential during fetal life or during the immediate perinatal period during which the production of fetal hemoglobin predominates
- Infants Begin to Manifest Clinical Symptoms During the Second 6 Months of Life: when gamma globin chain production normally decreases and is usually replaced with the production of beta globin to form adult hemoglobin -> however, patients with beta thalassemia major are unable to produce beta globin
- Variability of Clinical Manifestations: clinical manifestations are highly variable between patients (possibly related to differences in mutations with regard to beta globin production or co-existing alpha thalassemia)
Cardiac Manifestations
- Arrhythmias
- Supraventricular Arrhythmias
- Ventricular Arrhythmias
- Cardiac Hemosiderosis
- High-Output Congestive Heart Failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])
Endocrine Manifestations
- Diabetes Mellitus (see Diabetes Mellitus, [[Diabetes Mellitus]])
- Epidemiology
- Occurs in 13% of cases
- Impaired glucose tolerance usually appears during the second decade of life
- Physiology: the early onset of impaired glucose tolerance appears to be related more to insulin resistance than to defective insulin release
- Growth Failure/Retardation
- Epidemiology: occurs in 33% of cases
- Hypogonadism
- Epidemiology: occurs in 40% of cases
- Physiology: predicted by pituitary iron overload and pituitary volume loss
- Hypothyroidism (see Hypothyroidism, [[Hypothyroidism]])
- Epidemiology: occurs in 10% of cases
- Pituitary Iron Overload
- Epidemiology: occurs during the first decade of life
Gastrointesinal/Hepatic Manifestations
- Bilirubin Gallstone Disease
- Epidemiology
- Occurs in 66% of cases
- Occurs before age 15
- Biliary Tract Inflammation
- Cirrhosis (see End-Stage Liver Disease, [[End-Stage Liver Disease]])
- Physiology: due to iron overload (which may occur later in the first decade of life)
- Hepatomegaly (see Hepatomegaly, [[Hepatomegaly]])
- Epidemiology: occurs early in course of disease
- Physiology: due to increased red blood cell destruction and hepatic extramedullary hematopoiesis
- Hyperbilirubinemia/Jaundice (see Jaundice, [[Jaundice]])
- Physiology: due to severe hemolytic anemia
Hematologic Manifestations
- Aplastic Crisis
- Infection with Parvovirus B19 (see Parvovirus B19, [[Parvovirus B19]]): may have a disproportionate impact on these patients (due to shortened red blood cell survival)
- Hemolytic Anemia (see Hemolytic Anemia, [[Hemolytic Anemia]])
- Ineffective Erythropoiesis
- Clinical: with expansion and invasion of erythroid bone marrow with widening of marrow spaces and attenuation of cortex of the bone
- Iron Overload (see Iron Overload, [[Iron Overload]])
- Microcytic Anemia (see Anemia, [[Anemia]])
- Splenomegaly (see Splenomegaly, [[Splenomegaly]])
- Epidemiology: occurs early in the course of disease (due to increased red cell destruction and splenic extramedullary hematopoiesis)
- Clinical: may be massive
Infectious Manifestations
- Increased Risk of Infection (Especially Encapsulated Organisms)
- Physiology: due to loss of splenic immune function
Neurologic Manifestations
Pulmonary Manifestations
- Abnormal Pulmonary Function Tests (PFT’s)/Exercise Testing: for unclear reasons -> these defects correct with transfusion and do not correlate with the iron burden, blood counts, or degree of hemolysis
- Abnormal Anaerobic Threshold
- Decreased Maximal Oxygen Uptake
- Hyperinflation
- Restriction (see Pulmonary Function Tests, [[Pulmonary Function Tests]])
- Small Airways Obstructive Defects (see Obstructive Lung Disease, [[Obstructive Lung Disease]])
- Pulmonary Hypertension (see Pulmonary Hypertension, [[Pulmonary Hypertension]])
- Risk Factors
- Chronic Hemolysis
- Iron Overload
- Older Age
- Platelet Activation
- Prior Splenectomy
- Tobacco Abuse
- Physiology: unclear etiology
Renal Manifestations
- Dilated Renal Tubules
- Enlarged Kidneys
- Physiology: due to extramedullary hematopoiesis
- Hemosiderinuria (see Hemosiderinuria, [[Hemosiderinuria]])
- Increased Urinary Oxalate/Urate/Uric Acid
Rheumatologic/Orthopedic Manifestations
- Bony Abnormalities
- “Chipmunk Facies”
- Frontal Bossing
- Delayed Skeletal Maturation
- Osteoporosis (see Osteoporosis, [[Osteoporosis]])
Other Manifestations
Treatment
Packed Red Blood Cell (PRBC) Hypertransfusion (see Packed Red Blood Cells, [[Packed Red Blood Cells]])
Iron Chelation Therapy
- General Comments: start around 2 years of age (after about 1.5 years of transfusions)
- Deferasirox (Exjade) (see Deferasirox, [[Deferasirox]])
- Deferoxamine (Desferal, DFO) (see Deferoxamine, [[Deferoxamine]])
- Deferiprone (Ferriprox) (see Deferiprone, [[Deferiprone]])
Splenectomy
Bone Marrow/Stem Cell Transplant (see Bone Marrow Transplant, [[Bone Marrow Transplant]])
- Preferred Donor: HLA-matched sibling marrow or cord blood stem cells
- Allogeneic BMT: being studied
Pharmacologic Manipulation of Fetal Hemoglobin Levels
Gene Therapy
Prognosis
- Mortality in Untreated Cases: 80% of untreated children will die within the first 5 years of life (usually due to severe anemia, high output congestive heart failure, failure to thrive, and unsusual susceptibility to infection)
- Mortality in Treated Cases: survival into 50’s and beyond can be achieved with appropriate transfusion and iron chelation treatment
References