A microcytic anemia and elevated iron levels in tissues

An 8-year-old child has been brought to his pediatrician by his parents after they noticed that he felt very fatigued. They also noted that his abdomen seemed to be enlarged. Examination reveals an enlarged spleen. Further history reveals that the child been given vitamins and iron supplements over the last few months. Laboratory tests show a microcytic anemia and elevated iron levels in tissues.

Which of the following conditions is most consistent with the findings in this patient?

A. Aplastic anemia

B. Sickle cell anemia

C. Pernicious anemia

D. Thalassemia major

E. Thalassemia minor

The correct answer is E- Thalassemia minor.

Basic concept

The thalassemias are hereditary disorders characterized by reduction in the synthesis of globin chains (α or β). Reduced globin chain synthesis causes reduced hemoglobin synthesis and eventually produces a hypochromic microcytic anemia because of defective hemoglobinization of red blood cells.

Normal adult hemoglobin is primarily hemoglobin A, which represents approximately 98% of circulating hemoglobin. Hemoglobin A is formed from a tetramer—two α chains and two β chains—and can be designated α 2 β 2 (figure-1).

Structure of normal Hb

Figure-1- Structure of normal Hemoglobin (Hb A)

Two copies of the α -globin gene are located on chromosome 16, and there is no substitute for α -globin in the formation of hemoglobin. The β -globin gene resides on chromosome 11 adjacent to genes encoding the β -like globin chains, δ and γ (figure-2).The tetramer of α 2 δ 2 forms hemoglobin A2, which normally comprises 1–2% of adult hemoglobin. The tetramer α 2 γ 2 forms hemoglobin F, which is the major hemoglobin of fetal life but which comprises less than 1% of normal adult hemoglobin.

Alph and beta gene cluster

Figure-2- Alpha and beta globin gene clusters, Zeta  genes are expressed only in the early embryonic life

Types of Thalassemia

Based on the defective chain, there are two main types:

i) Alpha Thalassemia

Alpha thalassemia demonstrates defects with alpha globin chain production.

ii) Beta Thalassemia

Beta thalassemia demonstrates defects with beta globin chain production.

Alpha Thalassemia

Alpha Thalassemia are due primarily to gene deletion causing reduced α-globin chain synthesis (figure-3). The most common mechanism of aberrant α-globin production is due to deletions of either portions of the α-globin genes themselves or the genetic regulatory elements that control their expression.

Types of alpha thalassemia (figure-3)

  • Alpha (0) thalassemia –Individuals with this disorder are not able to produce any functional α-globin and thus are unable to make any of the functional hemoglobins like A, F, or A2. This leads to the development of Hydrops fetalis, also known as hemoglobin Bart, a condition that is incompatible with extra uterine life.
  • Alpha (+) thalassemia –There is decreased production of α-globin usually due to the functional deletion of 1 of the 4 alpha globin genes. Based on the number of inherited alpha genes, alpha (+) thalassemia is sub classified into 3 general forms:
    • A- Thalassemia (-α/α α) is characterized by inheritance of 3 normal α-genes. These patients are referred to clinically as silent carrier of alpha thalassemia. Other names for this condition are alpha thalassemia minima, alpha thalassemia-2 trait, and heterozygosity for alpha (+) thalassemia minor. The affected individuals exhibit no abnormality clinically and may be hematologically normal or have mild reductions in red cell mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH).
    • B- Inheritance of 2 normal alpha genes due to either heterozygosity for alpha (0) thalassemia (α α/–) or homozygosity for alpha (+) thalassemia (-α/-α) results in the development of alpha thalassemia minor or alpha thalassemia-1 trait. The affected individuals are clinically normal but frequently have minimal anemia and reduced mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH).
    • C- Inheritance of one normal alpha gene (-α/–) results in abundant formation of hemoglobin H composed of tetramers of excess beta chains. This condition is known as HbH disease. The affected individuals have moderate to severe lifelong hemolytic anemia, modest degrees of ineffective erythropoiesis, splenomegaly, and variable bony changes.

Alpha thalassemia

Figure-3- Alpha thalassemia- Genetics and clinical manifestations

β Thalassemia

β Thalassemias are usually caused by point mutations rather than deletions .These mutations result in premature chain termination and ultimately result in reduced or absent β -globin chain synthesis.

Types of Beta thalassemia

The molecular defects leading to β -thalassemia are numerous and heterogeneous. Defects that result in absent globin chain expression are termed β 0, whereas those causing reduced synthesis are termed β +. The reduced β -globin chain synthesis in β -thalassemia results in a relative increase in the percentages of hemoglobins A2 and F compared to hemoglobin A, as the β -like globins (δ and γ) substitute for the missing β chains (table) In the presence of reduced β chains, the excess α chains are unstable and precipitate, leading to damage of red blood cell membranes. This leads to intramedullary and peripheral hemolysis. The bone marrow becomes hyper plastic under the drive of anemia and ineffective erythropoiesis resulting from the intramedullary destruction of the developing erythroid cells. In cases of severe thalassemia, the marked expansion of the erythroid element in the bone marrow may cause severe bony deformities, osteopenia, and pathologic fractures (figure-4).

Table- Beta thalassemia syndromes

Beta thalassemia syndromesClinical Findings 


Thalassemia major

Affected children are normal at birth but after 6 months, when hemoglobin synthesis switches from hemoglobin F to hemoglobin A, develop severe anemia requiring transfusion. Numerous clinical problems ensue, including growth failure, bony deformities (abnormal facial structure, pathologic fractures), hepatosplenomegaly, and jaundice (figure-4).The clinical course is modified significantly by transfusion therapy, but the transfusional iron overload (hemosiderosis) results in a clinical picture similar to hemochromatosis, with heart failure, cirrhosis, and endocrinopathies, usually after more than 100 units of red blood cells. These problems develop because of the body’s inability to excrete the iron from transfused red cells. People with thalassemia major may also experience -Pallor, headaches, fatigue and shortness of breath.

The clinical manifestations are the direct result of the pathophysiologic process of thalassemia. Pallor is present because hemoglobin is a major factor in the normal skin color. Children with thalassemia are usually small for their age, reaching only the 5th percentile for growth. They experience recurrent severe anemia (hemoglobin 6 g/dL) and hepatosplenomegaly. The stress on the bone marrow causes the bones to thicken and become less flexible. This leads to pathological fractures and pain. If a child is well for the first five years of life, a diagnosis of Thalassemia Major is unlikely.

Beta thalassemia

Figure-4- Clinical manifestations in thalassemia

Thalassemia Intermedia

Patients homozygous for a milder form of β -thalassemia (allowing a higher rate of globin gene synthesis) have thalassemia Intermedia. These patients have chronic hemolytic anemia but do not require transfusions except under periods of stress. They may also develop iron overload because of periodic transfusion. They survive into adult life but with hepatosplenomegaly and bony deformities. Patients heterozygous for β -thalassemia have thalassemia minor and a clinically insignificant microcytic anemia.

β Thalassemia minor

As in α -thalassemia trait, these patients have a modest anemia. The peripheral blood smear is mildly abnormal, with hypochromia, microcytosis, and target cells (figure-5). The general symptoms of anemia are there. Generally no treatment is recommended, as iron supplementation leads to iron load.

PBF Thalassemia minor

Figure-5- Microcytic hypochromic anemia in thalassemia minor


The thalassemia have a distribution concomitant with areas were malaria is common. People with Thalassemia Minor are able to fight malaria better than those who do not have it – therefore, in parts of the world where malaria existed, Thalassemia Minor increased. This was of great value in the past since malaria was rampant and deadly. The beta thalassemias are seen primarily in the Mediterranean Sea area, Africa and Southeast Asia. Due to global migration patterns, there has been an increase in the incidence of thalassemia in North America in the last ten years. Thalassemia has also been found in people of many ethnic backgrounds, so it cannot be called a Mediterranean disease. Other areas affected are the Mid East, India, Pakistan and Southeast Asia.

The child in the given case has Thalassemia minor. The clinical picture of thalassemia major is more severe .This condition is characterized by transfusion-dependent anemia, massive splenomegaly, bone deformities, growth retardation, and peculiar facies in untreated individuals, 80% of whom die within the first 5 years of life from complications of anemia

It is not aplastic anaemia, sickle-cell or pernicious anemia, because the peripheral blood picture shows microcytic hypochromic anemia. Aplastic anemia is a syndrome of bone marrow failure characterized by peripheral pancytopenia and marrow hypoplasia. Although the anemia is often normocytic, mild macrocytosis can also be observed. In sickle-cell anemia, the peripheral blood film shows the presence of sickled red blood cells and in pernicious anemia, which occurs due to B12 deficiency, macrocytic anemia is observed.

Thus, Thalassemia minor is the most suitable diagnosis for this patient.





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