Thalassemia intermedia


Thalassemia intermedia

Description, Causes and Risk Factors:

Abbreviation: TI.

Thalassemia intermedia (TI) was first illustrated in 1955 by RiettiGreppi-Micheli, who described patients as being `too hematologically severe to be called minor, but too mild to be called major'. Our knowledge of the molecular basis of thalassemia intermedia has progressed significantly in the last decade, including an increased understanding of the genetic mutations that lead to the thalassemia intermedia phenotypes.

The clinical manifestations of thalassemia result from defects in one of two types of polypeptide chains (alpha or beta). For hemoglobin to function properly, the number of alpha-chains must precisely match the number of beta-chains. Thalassemia is caused by an imbalance in globin chain synthesis. The beta-thalassemias (-thalassemias) including thalassemia intermedia, arise from defective gene function leading to the partial suppression of beta-globin protein production. The extent of suppression varies from patient-to-patient and dictates the clinical disease severity. Most thalassemia intermedia patients are homozygotes or compound heterozygotes for beta-thalassemia, meaning that both beta-globin loci are affected. Less commonly, only a single beta-globin locus is affected, the other being completely normal. The mild clinical characteristics of thalassemia intermedia compared with thalassemia major result primarily from three different mechanisms.

    Inheritance of a mild or silent beta-chain mutation: Rather than a complete absence of beta-chain synthesis, the level of synthesis is subnormal. This leads to a smaller imbalance between the number of alpha- and beta-chains compared with an absence of beta-chains.

  • Co-inheritance of determinants associated with increased gamma-chain production: The increased number of gamma-chains helps to neutralize the large proportion of unbound alpha-chains.

  • Co-inheritance of alpha-thalassemia: This helps to suppress the synthesis of alpha-chains, causing less of an alpha/beta-chain imbalance.

Three main factors are responsible for the clinical sequelae of thalassemia intermedia may include ineffective erythropoiesis, chronic anemia and iron overload. The severity of clinical sequelae primarily depends on the underlying molecular defects. Alpha-chains are highly unstable and precipitate into erythroid precursors in the bone marrow, causing membrane damage and cell death — this is ineffective erythropoiesis. Hypertrophy of erythroid marrow in medullary and extramedullary sites, a consequence of severe ineffective erythropoiesis, results in characteristic deformities of the skull and face and may also cause cortical thinning and pathological fractures of long bones. The degree of ineffective erythropoiesis is the primary determinant of the development of anemia, while peripheral hemolysis of mature red blood cells and an overall reduction in hemoglobin synthesis are secondary. Chronic anemia leads to an increase in gastrointestinal iron absorption, resulting in iron overload that can cause a number of serious complications including cardiac failure and endocrine abnormalities such as diabetes mellitus and hypogonadism.

People who carry the thalassemia trait do not have ill effects from the carrier state and usually are unaware that they carry it. They may be told that they are slightly anemic and have “small red blood cells”.

In order for a child to get thalassemia intermedia, both parents must carry the trait for thalassemia. If both parents carry the trait (also known as “thalassemia minor”), there is a 1-in-4 chance with each pregnancy that the child will be born with the severe form of the disease.

Thalassemia intermedia encompasses a wide clinical spectrum. Mildly affected patients are completely asymptomatic until adult life, experiencing only mild anemia and maintaining hemoglobin levels between 7 and 10 g/dL. These patients require only occasional blood transfusions, if any. Patients with more severe thalassemia intermedia generally present between the ages of 2 and 6 years, and although they are able to survive without regular transfusion therapy, growth and development can be retarded. The clinical spectrum of thalassemia intermedia indicates the need for an individualized treatment approach.

Analysis of the genotypes of patients with thalassaemia intermedia is important for an early diagnosis of the milder disease, thus avoiding unnecessary blood transfusions. Despite the availability of a number of treatment options, the lack of clear guidelines can present a significant clinical challenge.

Symptoms:

The following are some of the possible symptoms that are presented by patients with this kind of ailment: Anemia, weakness, pallor, fatigue, syncope, breathing difficulties (breathlessness), poor tolerance to exercise, stomach pain as a result of problems with the spleen or of the gallbladder, poor growth, jaundice, maxillary hyperplasia, dental malocclusions, non-pathologic fractures, and cholelithiasis.

Diagnosis:

Predicting phenotype from genotype in TI is still difficult, due to the interaction of genetic and environmental factors. Diagnostic tests are necessary to determine if a patient does have thalassemia intermedia. These diagnostic tests include:

    Blood studies (CBC, hemoglobin electrophoresis).

  • Family history - since thalassemia is a familial disease, it is important to look at a patient's family history.

  • DNA Testing - can help determine if a patient does have thalassemia and can also find out carrier status.

  • Genetic testing.

Treatment:

Unlike in thalassemia major, where the degree of severity of anemia is more uniform from patient to patient, there is a great deal of variation in the severity of the anemia associated with thalassemia intermedia. All patients with thalassemia intermedia experience some form of decreased hemoglobin levels.

In children with thalassemia intermedia, there are many decisions to be made by the health care team and the family in terms of transfusion. Frequently, your child's doctor will only give transfusions if the hemoglobin falls below a certain value on several occasions. Other times the team will decide to give chronic transfusion for a certain time period and then re-evaluate. These decisions depend on the well-being of your child and how he or she feels. It is hard to predict in what category your child will fall; therefore, the child will require frequent check-ups with your doctor.

There are a number of complications that may or may not occur, depending upon the severity of the anemia and upon the course of treatment that is best for your child. Let's assume your child does not require transfusions. You may notice some “bony changes” in the face; the forehead or the cheek bones may appear to protrude, or he or she may appear to have “buck teeth”. These changes are due to the bone marrow working extra hard to make red blood cells. This extra work causes the cells to “expand” in these areas. As your child gets older, he or she may experience broken bones more easily. Again, this is due to the extra work in the bone marrow.

Some patients develop hypersplenism, if their bodies attempt to create more red blood cells outside the bone marrow.

Although thalassemia intermedia are not chronically transfused as are thalassemia major patients, they still may develop iron overload. They therefore should avoid foods with high iron concentrations and iron supplements. If their iron levels reach a certain level, iron chelation therapy may be required.

Delayed puberty, impaired growth, gallstones and osteoporosis may also occur in older children with thalassemia intermedia. There is also some evidence that thalassemia intermedia patients, especially those who have had their spleens removed, may have a slightly greater risk of blood clots.

Because there are so many potential complications associated with thalassemia, patients should undergo an annual “comprehensive care evaluation.” This should be performed at a Thalassemia Center of Excellence, each of which has a team of experts from different disciplines with significant experience in thalassemia.

NOTE: The above information is educational purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.

DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.

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