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Thalassemia Anemia (Alpha-thalassemia & Beta-thalassemia)

The thalassemia syndromes are a heterogeneous group of inherited anemias characterized by defects in the synthesis of one or more globin chain subunits of the adult hemoglobin tetramer (Hb A).This leads to deficient hemoglobin accumulation, resulting in hypochromic and microcytic red cells & ineffective erythropoiesis and hemolytic anemia.

SIGNS AND SYMPTOMS:

• Thalassemia trait has no signs or symptoms.
• Pallor, Poor growth, Inadequate food intake, Fatigue, Shortness of breath, Splenomegaly, Jaundice, Maxillary hyperplasia, Dental malocclusion, Cholelithiasis, Pathologic fractures

LABORATORY

In the presence of normal iron status, increased levels of Hb A2 (to 4 to 6%) and/or increased Hb F (to 5 to 20%) by quantitative hemoglobin analysis supports the diagnosis. Unfortunately, differentiation between iron deficiency anemia and beta- or alpha-thalassemia trait can be difficult in practice if no reciprocal increases in Hb A2 levels and/or Hb F are present.   Moreover, in the presence of concomitant iron deficiency, Hb A2 levels in beta-thalassemic individuals may fall into the normal range. In these instances, the demonstration of a modified beta/alpha-globin synthetic chain ratio, generally using 3 H-leucine to analyze globin chain production in reticulocytes, would be required for a conclusive diagnosis.

The distinction between alpha- and beta-thalassemia depends on the measurement of the minor hemoglobins Hgb A2 & Hgb F.  If these are normal, the diagnosis of alpha-thalassemia is most likely, although rare subjects with beta-thalassemia also have normal levels of Hb A2 and Hb F.

Hemoglobin electrophoresis:

• Elevated Hb A2 levels in beta-thalassemia trait
• Elevated Hb A2, elevated Hb F, reduced or absent Hb A1 in beta-thalassemia major or intermedia

Peripheral blood:

• Pronounced microcytosis, Anisocytosis, Poikilocytosis, Hypochromia, Punctate basophilic stippling, High percentage of target cells, nucleated RBC, Reticulocyte count elevated

Hematocrit:

• 28-40% in alpha-thalassemia trait and beta-thalassemia trait
• May fall to less than 10% in beta-thalassemia major

DIFFERENTIAL DIAGNOSIS

A characteristic feature of beta-thalassemia trait is elevation of the level of Hb A2 . This minor hemoglobin accounts for only 2 or 3% of the total in normal red cells, but in thalassemia trait it may be elevated in the range of 4 to 8% in more than 90% of persons with this condition. Similarly, the level of Hb F is often elevated to 1.5 to 2.5%, although in rare types of thalassemia trait it may be as high as 10 to 15%. In normal red cells, Hb F accounts for less than 1% of the total. The minor hemoglobins, Hb A2 and Hb F, are either normal or slightly decreased in patients with alpha-thalassemia.

The differential diagnosis of thalassemia trait includes consideration of iron deficiency. This diagnosis can be excluded only by measurement of the serum iron, total iron-binding capacity, and serum ferritin. If these values are normal in patients whose red cells are severely microcytic, but in whom anemia, if present, is mild, the diagnosis of thalassemia trait can be considered established.

Alpha-thalassemia - there is deficient synthesis of alpha globin.
Individuals with decreased function of one or two of the four alpha-globin genes may have only mild microcytosis or a mild hypochromic microcytic anemia (Hb >10 g/dl), usually are asymptomatic.
A deletion or mutation of three alpha-globin genes results in Hb H disease, which is characterized by splenomegaly, moderately severe chronic hemolytic anemia with Hgb of 8 - 10 g/dL, a hypochromic, microcytic blood film appearance.  Hb H (beta4 ) is demonstrable by special staining of the red cell and by hemoglobin electrophoresis. and the presence of beta-globin tetramers.   The same drugs that induce hemolysis in glucose-6-phosphate dehydrogenase-deficient patients, especially the sulfonamides, should be avoided in susceptible patients with Hb H disease.
A loss of all four alpha-globin genes  is incompatible with life, and the fetus is stillborn or critically ill with hydrops fetalis.
These disorders have their highest prevalence in blacks (up to 30%), in whom a single alpha-gene or two alpha-genes in trans (opposite chromosomes) may be deleted. In contrast, in Southeast Asian populations, where the prevalence may reach up to 40%, more typically two alpha-genes in cis (on the same chromosome) may be deleted, although single alpha-gene deletions are also seen.

Beta-thalassemia - there is deficient synthesis of beta globin  
The condition is ubiquitous, but especially common in Mediterranean, Asian, and African populations (and their American descendants).  
- Ineffective erythropoiesis in the bone marrow and enhanced peripheral RBC destruction.
- Splenomegaly, which may lead to hypersplenism,
- Osteoporosis, and other skeletal and soft tissue changes associated with an expanded bone marrow, and
- Iron overload resulting from a combination of enhanced gastrointestinal iron absorption and red cell transfusions. The liver, heart, pancreas, pituitary, and other endocrine organs serve as the major sites of excessive iron deposition, which ultimately leads to damage and failure of these organs.

Production of beta-globin chains may be reduced or absent from each allele and are described as beta+ -thalassemia or beta°-thalassemia, respectively.

Beta-thalassemia commonly is classified by the severity of anemia; many genotypes exist for each phenotype.
1.  Thalassemia minor (trait) is caused by diminished or absent beta-globin chain synthesis from one gene. Patients are asymptomatic with a hypochromic microcytic anemia (Hb >10 g/dl).
2.  Thalassemia intermedia usually is associated with dysfunction of both beta-globin genes. Clinical severity is intermediate (Hb 7-10 g/dl), and patients usually are not transfusion dependent.
3.  Thalassemia major (Cooley's anemia) is caused by severe dysfunction of both beta-globin genes. Severe anemia, growth retardation, hepatosplenomegaly, bone marrow expansion and bone deformities. Transfusion therapy necessary to sustain life.

Varieties unique to Southeast Asians include hemoglobin H disease (a more severe form of alpha thalassemia) and hemoglobin E/beta thalassemia which often mimics Beta thalassemia major in its severity. Both alpha and beta thalassemia trait (minor) are frequent in African-Americans but symptomatic thalassemia is very rare.

Genetics: Inherited in an autosomal recessive pattern.   Inheritance of one defective gene = milder type of thalassemia, two defective genes = severe type of thalassemia

Therapy for severe Thalassemia disease (Mild cases require no therapy)

1. Transfusions to an Hb of more than 9 g/dl prevents skeletal deformities and usually can be achieved with 1 unit of RBCs every 2-3 weeks or 2 units every month.
2. Splenectomy removes the primary site of extravascular hemolysis and should be considered if RBC transfusion requirements increase and exceed 1.5 times the previous levels.   It should not be performed if the patient is younger than 5-6 years because of the risk of sepsis. To decrease the risk of postsplenectomy sepsis, immunization against pneumococci and Haemophilus influenzae should be administered 1 month before surgery if not done previously.
3. Iron chelation therapy with deferoxamine mesylate, 50-100 mg/kg per day, usually is administered by continuous SC infusion for 10-12 hours/day. If started in infants when the iron burden is very low, growth failure is possible, so chelation therapy is recommended to begin at age 5-6 years; most patients will achieve normal growth and sexual development. Once clinical organ deterioration has begun, it may not be reversible. Therapy may be complicated by local irritation at the injection site, and pruritus and hypotension may occur if the drug is infused too rapidly. Continuous IV infusion of deferoxamine through an indwelling venous catheter at the same dosage and schedule also may be used ( Am J Hematol 41:61, 1992). Although generally safe, long-term side effects, particularly with high-dose therapy, include optic  neuropathy, sensorineural hearing loss, and increased risk of infection. Patients receiving deferoxamine should have baseline and yearly vision and hearing examinations. Vitamin C supplementation, 100 mg PO, given during the infusion of deferoxamine will increase urinary iron excretion approximately twofold during chelation therapy but generally is not needed during long-term chelation therapy.
4. Bone marrow transplant should be considered in young patients who have thalassemia major and have HLA-identical related donors.
5. Administer polyvalent pneumococcal vaccine one month prior to splenectomy;  Folate supplementation.
6. Prophylaxis with a daily regimen of penicillin;  Treat infections promptly .

ACTIVITY

• Avoid strenuous activities (e.g., football, soccer)
• Acceptable activity levels will need to be determined on an individual basis depending on severity of disorder

DIET

• Avoid iron-rich foods (meats such as liver, and some cereals)
• Drinking tea may possibly help reduce iron

PATIENT EDUCATION

• Genetic counseling
• Teach parents signs of hepatitis, iron overload
• Printed patient information available from: Cooley's Anemia Foundation,
  105 E. 22nd St., Suite 911, New York, NY 10010, (212)598-0911

Ref:
Goldman: Cecil Textbook of Medicine, 21st Ed. 2000
Dambro: Griffith's 5-Minute Clinical Consult, 1999
Washington Manual of Medical Therapeutics, 29th ed., 1998

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

The prevalence of G6PD deficiency in African black, Mediterranean, Indian, and Southeast Asian populations is thought to derive from the relative protection afforded G6PD heterozygotes against Plasmodium falciparum malaria.

Classification:
A mild form of the deficiency occurs in perhaps 10% of black men and is characterized by hemolytic episodes triggered by infections or drug exposure. A more severe enzyme deficiency, such as the Mediterranean variety, results in hemolysis when susceptible individuals are exposed to fava beans. The most severe type causes a chronic hereditary nonspherocytic hemolytic anemia in the absence of an inciting cause.

Laboratory results:
The peripheral smear shows "bite cells"; RBC inclusions (Heinz bodies) are seen with special stains. Measurement of enzyme levels usually establish the diagnosis. However, senescent RBCs contain less G6PD and are destroyed more easily than are younger cells, so that after a hemolytic episode, the G6PD level may be normal, reflecting the younger population of cells in the circulation.
Hemoglobin electrophoresis test may show deficiency of the G6PDH.

Treatment consists of adequate hydration to protect renal function during hemolysis, avoidance of precipitating factors and, if necessary, RBC transfusion.

Because all but a few rare individuals with G6PD deficiency are hematologically normal in the absence of an exogenous oxidant stress, no treatment is required for the deficiency itself.  Mild to moderate episodes of acute hemolysis can often be managed by removal of the offending drug or by treatment of the concurrent infection. Severe hemolytic episodes in individuals with GdMed and other unstable G6PD variants may require red cell transfusions to alleviate the signs and symptoms of acute anemia, as well as measures designed to protect against the potential renal complications of hemoglobinuria.

Ref:
Washington Manual of Medical Therapeutics, 29th ed., 1998
Goldman: Cecil Textbook of Medicine, 21st Ed.,  2000

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