The Thalassemias
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Introduction
• Heritable, hypochromic anemias-varying degrees of severity
• Genetic defects result in decreased or absent production of mRNA and globin chain synthesis
• At least 100 distinct mutations
• High incidence in Asia, Africa, Mideast, and Mediterrenean countries
Hemoglobin Review
• Each complex consists of :
– Four polypeptide chains, non-covalently bound
– Four heme complexes with iron bound
– Four O2 binding sites
Globin Chains
• Alpha Globin
– 141 amino acids
– Coded for on Chromosome 16
– Found in normal adult hemoglobin, A1 and A2
• Beta Globin
– 146 amino acids
– Coded for on Chromosome 11, found in Hgb A1
• Delta Globin
– Found in Hemoglobin A2--small amounts in all adults
• Gamma Globin
– Found in Fetal Hemoglobin
• Zeta Globin
– Found in embryonic hemoglobin
Hemoglobin Types
Hemoglobin Type
• Hgb A1—92%---------
• Hgb A2—2.5%--------
• Hgb F — <1%---------
• Hgb H ------------------
• Bart’s Hgb--------------
• Hgb S--------------------
• Hgb C-------------------
Globin Chains
a2b2
a2d2
a2g2
b4
g4
a2b26 gluàval
a2b26 gluàlys
Genetics
• Alpha globins are coded on chromosome 16
– Two genes on each chromosome
– Four genes in each diploid cell
– Gene deletions result in Alpha-Thalassemias
• Also on chromosome 16 are Zeta globin genes—Gower’s hemoglobin (embryonic)
• Beta globins are coded on chromosome 11
– One gene on each chromosome
– Two genes in each diploid cell
– Point mutations result in Beta-Thalassemias
• Also on chromosome 11 are Delta (Hgb A2) and Gamma (Hgb F) and Epsilon (Embryonic)
Alpha Thalassemias
• Result from gene deletions
• One deletion—Silent carrier; no clinical significance
• Two deletions—a Thal trait; mild hypochromic microcytic anemia
• Three deletions—Hgb H; variable severity, but less severe than Beta Thal Major
• Four deletions—Bart’s Hgb; Hydrops Fetalis; In Utero or early neonatal death
Alpha Thalassemias
• Usually no treatment indicated
• 4 deletions incompatible with life
• 3 or fewer deletions have only mild anemia
Beta Thalassemias
• Result from Point Mutations on genes
• Severity depends on where the hit(s) lie
– b0-no b-globin synthesis;
– b+ reduced synthesis
• Disease results in an overproduction of a-globin chains, which precipitate in the cells and cause splenic sequestration of RBCs
• Erythropoiesis increases, sometimes becomes extramedullary
b-Thal--Clinical
• b-Thalassemia Minor
– Minor point mutation
– Minimal anemia; no treatment indicated
• b-Thalassemia Intermedia
– Homozygous minor point mutation or more severe heterozygote
– Can be a spectrum; most often do not require chronic transfusions
• b-Thalassemia Major-Cooley’s Anemia
– Severe gene mutations
– Need careful observation and intensive treatment
Beta Thalassemia Major
• Reduced or nonexistent production of b-globin
– Poor oxygen-carrying capacity of RBCs
• Failure to thrive, poor brain development
– Increased alpha globin production and precipitation
• RBC precursors are destroyed within the marrow
• Increased splenic destruction of dysfunctional RBCs
– Anemia, jaundice, splenomegaly
• Hyperplastic Bone Marrow
– Ineffective erythropoiesis—RBC precursors destroyed
• Poor bone growth, frontal bossing, bone pain
– Increase in extramedullary erythropoiesis
• Iron overload—increased absorption and transfusions
– Endocrine disorders, Cardiomyopathy, Liver failure
b-Thalassemia Major—Lab findings
• Hypochromic, microcytic anemia
– Target Cells, nucleated RBCs, anisocytosis
• Reticulocytosis
• Hemoglobin electrophoresis shows
– Increased Hgb A2—delta globin production
– Increased Hgb F—gamma globin production
• Hyperbilirubinemia
• LFT abnormalities (late finding)
• TFT abnormalities, hyperglycemia (late endocrine findings)
b-Thalassemia Major--Treatment
• Chronic Transfusion Therapy
– Maximizes growth and development
– Suppresses the patient’s own ineffective erythropoiesis and excessive dietary iron absorption
– PRBC transfusions often monthly to maintain Hgb 10-12
• Chelation Therapy
– Binds free iron and reduces hemosiderin deposits
– 8-hour subcutaneous infusion of deferoxamine, 5 nights/week
– Start after 1year of chronic transfusions or ferritin>1000 ng/dl
• Splenectomy--indications
– Trasfusion requirements increase 50% in 6mo
– PRBCs per year >250cc/kg
– Severe leukopenia or thrombocytopenia
b-Thalassemia Major Complications and Emergencies
• Sepsis—Encapsulated organisms
– Strep Pneumo
• Cardiomyopathy—presentation in CHF
– Use diuretics, digoxin, and deferoxamine
• Endocrinopathies—presentation in DKA
– Take care during hydration so as not to precipitate CHF from fluid overload
Anticipatory Guidance and Follow Up
• Immunizations—Hepatitis B, Pneumovax
• Follow for signs of diabetes, hypothyroid, gonadotropin deficiency
• Follow for signs of cardiomyopathy or CHF
• Follow for signs of hepatic dysfunction
• Osteoporosis prevention
– Diet, exercise
– Hormone supplementation
– Osteoclast-inhibiting medications
• Follow ferritin levels
On The Horizon
• Oral Chelation Agents
• Pharmacologically upregulating gamma globin synthesis, increasing Hgb F
– Carries O2 better than Hgb A2
– Will help bind a globins and decrease precipitate
• Bone Marrow transplant
• Gene Therapy
– Inserting healthy b genes into stem cells and transplanting
This post was written by: Franklin Manuel
Franklin Manuel is a professional blogger, web designer and front end web developer. Follow him on Twitter
