Thalassemia: Pathophysiology, Diagnosis and Therapy (March 2004)

The thalassemias are the most common single gene disorders of humans, affecting over 12.5 million people worldwide. Thalassemia protects against malaria and is most prevalent where malaria is endemic. Immigration has resulted in an increase of thalassemia in North America.

Pathophysiology
Thalassemias are due to impaired production of globin chains, creating an uneven balance between hemoglobin’s alpha and beta chains. Patients with beta thalassemia do not produce enough beta globin chains and those with alpha thalassemia do not produce enough alpha chains. The precipitation of remaining globin chains alters the red cell, leading to its early destruction.

Beta thalassemia: Genotypes are classified as a complete absence of b-globin: b zero thalassemia (b-0), or a reduction in synthesis: b plus thalassemia (b+). There are four clinical syndromes:

1) Beta Thalassemia Major
Genotype: BO/BO or BO/B+ or B+/B+ or HbE/B0
Hb Electrophoresis: elevated HbA2 and HbF, no HbA
Clinically: Hb <7 g/dl, chronic transfusions required

2) Thal Intermedia
Genotype: BO/BO or BO/B+ or B+/B+ or HbE/B0 or HbE/B+
Hb Electrophoresis: elevated HbA@ and HbF, some HbA
Clinically: Hb 7-9 g/dl, intermittent transfusions initially, may become transfusion dependent later in life

3) Beta Thal Trait
Genotype: B/B+ or B/B0
Hb Electrophoresis: elevated HbA2 and HbF, if no iron, Vitamin B12, folate deficiency
Clinically: Hb > 9.5 - 10 g/dl, low MCV, genetic counseling

4) Silent Beta Thal Carrier
Genotype: B/B+ or B/BO
Hb Electrophoresis: elevated HbA2 and HbF
Clinically: normal red cell indices

Alpha thalassemia Normally we inherit four alpha globin genes, two from each parent. Alpha chain genotype is stated as aa/aa. Most alpha mutations are gene deletions. Four clinical syndromes emerge, as shown below.

1) Alpha Thalassemia Major (Hb Barts/Hydrops Fetalis)
Genotype: --/--
Hb Barts (70-90%, newborn), HbH
Clinically: severely anemic and hydropic in utero; most result in spontaneous abortion; transfusion dependent

2) Hgb H Disease
Genotype: a-/--
Hb Electrophoreses: Hb Barts (20-30%, newborn), HbH (10-15%, child-adult)
Clinically: Hb 7-9 g/dl; transfusions during oxidative stress; splenectomy for severe anemia

3) Alpha Thal Carrier
Genotype: aa/-- cis, a-/a- trans
Hb Electrophoresis: Hb Barts (2-10%, newborn), nl in adult, (need DNA testing)
Clinically: low MCV, possible mild anemia, genetic counseling with cis deletion

4) Alpha Thal Silent Carrier
Genotype: aa/a-
Hb Electrophoresis: Hb Barts (1-2%, newborn), nl in adult, (need DNA testing)
Clinically: normal red cell indices

Diagnosis
Prenatal Diagnosis—Early diagnosis of severe thalassemia is essential. A complete blood count should be obtained in all women in their reproductive years. If red cell indices are suggestive of a hemoglobinopathy (MCH <27 pg or MCV<82 fl) or if the woman is in a high-risk ethnic group, further screening with hemoglobin electrophoresis and quantitative HbA2 should be considered.

Postnatal Diagnosis—Newborn screening picks up many patients with thalassemias. Hb Barts (g4) in alpha thalassemia or an elevated Hb A2 or Hb F in beta thalassemia suggest these diagnoses. DNA-PCR analysis and parental testing further specify type and severity of disease.

Thalassemia should be suspected in anyone with a microcytic or hypochromic anemia (MCV<80 fl or MCH <27 pg). Hemoglobin electrophoresis with elevated Hb A2 and Hb F suggests beta thalassemia. Hb H (b4) suggests alpha thalassemia. Even if hemoglobin evaluation is normal, an alpha thalassemia trait still must be entertained. A DNA-PCR analysis can be performed, especially in those of Southeast Asian descent. Other causes for microcytic anemia include iron deficiency and lead toxicity. Iron deficiency is distinguished from thalassemia by a high free erythrocyte protoporphyrin level and a low ferritin, among other indices. Hb A2 and Hb F may be decreased in iron deficiency and mask beta thalassemia. Therefore, an iron deficient patient should be treated prior to accurately interpreting thalassemia studies. Referral to a hematologist should be considered if anemia persists after iron deficiency is corrected.

Therapy
Transfusions: Chronic transfusion therapy eliminates many complications of severe thalassemia by treating anemia and suppressing erythropoiesis. Side effects (infection, iron overload and emotional impact) make the decision a difficult one. The decision to transfuse is based on anemia severity and clinical assessment. Those who require chronic transfusion therapy typically present in the first six months of life with hemoglobins less than 7 g/dl, poor growth, splenomegaly and evidence of marrow expansion. A typical regimen is to transfuse every 3-4 weeks and maintain baseline, pretransfusion hemoglobin of 9.5 to 10.5 g/dl and post-transfusion hemoglobin of 13-13.5 g/dl.

Splenectomy: Hypersplenism may increase transfusion needs by up to30%. Splenectomy decreases transfusion requirements but has significant risks. Surgical risks and post-splenectomy sepsis are well-known complications. Pilot studies suggest that pulmonary vascular disease, thrombosis and disturbance to iron transport may be long-term risks. Family education concerning fever and the risk of life-threatening infection must be done. Vaccinations, timely evaluation and antibiotic treatment when febrile, and penicillin prophylaxis are essential to preventing sepsis.

A disease of iron overload
Chronic transfusion therapy has changed thalassemia major into a disease of iron overload. One unit of packed red cells delivers 175 mg of iron. Iron overload ultimately leads to generation of free hydroxyl radicals that cause cellular damage. Multiple attendant complications arise involving the cardiac, hepatic, endocrine and skeletal systems. Chelation with parenteral desferrioxamine is a necessary adjunct to chronic transfusion therapy. Oral chelating agents such as deferiprone (L1) are undergoing investigation.

Alternative therapies for thalassemia major and intermedia are developing. Bone marrow transplant is the only cure available for thalassemia at this time and is suggested for thalassemia major patients with a matched sibling. Research using medications for fetal hemoglobin augmentation are ongoing. Gene therapy and manipulation are possible future strategies.



This information provided by California Pacific Medical Center’s Division of Pediatric Hematology/Oncology
Physicians: Yisheng Lee, M.D., Louise Lo, M.D., and Yung Yim, M.D.,
Tel. (415) 600-3268