What Is Thalassemia Intermedia?

Thalassemia intermedia is an inherited genetic blood disorder. It is a milder form of thalassemia, wherein there is a reduced production of “adult” hemoglobin, which leads to anemia. It means that your child has a missing ingredient to create a normal adult hemoglobin.

Thalassemia intermedia is less severe than thalassemia major, which needs a long-term transfusion of red blood cells. DNA testing cannot reliably identify if your child has either thalassemia intermedia or thalassemia major. It is usually determined by your child’s transfusion needs. 

Thalassemia intermedia was first described by Rietti-Greppi-Micheli in 1955. Patients with the condition were described as “too hematologically severe to be called minor, but too mild to be called major.” Information about thalassemia intermedia’s molecular basis has significantly progressed over the years, which include an increased understanding of gene mutations that often lead to the phenotypes of thalassemia intermedia. 

Symptoms of thalassemia intermedia usually develop later in life around two years of age. Children with thalassemia intermedia are moderately anemic. However, many patients seem to survive without regular blood transfusions. The severity of thalassemia usually depends on the patient's hemoglobin levels and growth rate or development.

Thalassemia intermedia is known to develop in the same individual who has two or more forms of thalassemia. The severity of the condition also depends on different mutations.

For children to get thalassemia intermedia, both parents must have the thalassemia trait. When both parents carry the thalassemia minor trait, there is a 1 out of 4 chances that their child will get the severe form of the condition. Carriers of the thalassemia trait are usually unaware that they carry such trait since they do not have noticeable symptoms. However, they may be slightly anemic or have small RBCs. 

Although transfusion is not required in thalassemia intermedia, patients can get serious complications due to the progression of anemia. Complications include:

• Ineffective erythropoiesis
• Dietary iron absorption
• Anemia
• Inadequate transfusion

A person with thalassemia intermedia suffers from:

• Endocrinopathies
• Bone changes
• Heart disease
• Pulmonary hypertension
• Osteoporosis
• Chronic bone and joint pain

Intervention and initiation of treatment are affected by these complications. Treatment modalities involve the following:

• Supportive treatment
• Blood transfusions
• Medications to increase hemoglobin F synthesis
• Splenectomy

Complications such as pulmonary hypertension, gallstones, osteoporosis, and iron overload should be given special attention.

The clinical phenotypes of thalassemia intermedia are said to lie between thalassemia minor and thalassemia major. Affected individuals may remain asymptomatic until adult life. Such patients have a hemoglobin level between 7-10 g/dL and have mild anemia. Occasional blood transfusions may be done but only when required.

Most children between the ages of 2-6 years old with thalassemia intermedia tend to survive even without regular blood transfusions. However, they can have retarded growth and development. According to the clinical spectrum of thalassemia intermedia, an individualized treatment approach may be required in such cases.

Clinical Definition 

There are various forms of thalassaemia intermedia. There are some similarities in the clinical phenotypes of thalassemia minor, major, and intermedia. Based on clinical presentation alone, it is difficult to identify thalassemia intermedia. Thus, certain differentiating parameters have also been established. Thalassemia intermedia is usually characterized by:

• A hemoglobin level of 7-10 g/dL
• No regular blood transfusions
• Severe red blood cell (RBC) abnormality
• Enlarged spleen 
• Skeletal (bone) changes in the face, obliteration of maxillary sinuses, and a protruded upper jaw
• Molecular definition and mechanism of thalassemia intermedia

Hemoglobin has two pairs of globin chains. Adults normally have a pair of alpha chains and one pair of the beta chains. However, sometimes, one or several of these chains are abnormal. Thalassemia is usually categorized based on the affected amino acid chain. When the alpha globin chain is affected, it is called as alpha thalassemia, and when the beta globin chain is the one affected, it is called as beta-thalassemia.

Alpha thalassemia is commonly observed in Blacks, wherein 25 percent of the population carry at least a single copy of the problematic gene. Beta-thalassemia, on the other hand, is more common in people with a Mediterranean and Southeast Asian descent.

Thalassemia can also be categorized according to the number of defective gene copies that people possess:

• Thalassemia Minor: One defective gene copy

• Thalassemia Major: Two defective gene copies

Thalassemia is due to an imbalance in the globin chain synthesis. The number of alpha chains and beta chains must precisely match for the hemoglobin to function properly. Due to a defect in the gene function, beta thalassemia along with thalassemia intermedia arises. The beta-globin protein production is partially suppressed. However, the extent of suppression is different for each patient. Thus, the clinical severity also varies.

Many studies have attempted to classify thalassemia intermedia patients based on the severity of their condition, but with limited success. There was a recent study done in which thalassemia intermedia patients were successfully subclassified through a phenotype scoring system. Below is a list of considered clinical features:

• Age of presentation
• Extent of growth retardation
• Blood transfusion requirement
• Severity of anemia
• Need for splenectomy

For relating genotype to phenotype, this classification is said to be quite helpful. Also for different disease severities to develop a separate treatment guideline this classification could help.

Clinical Sequelae of Thalassaemia Intermedia

For the clinical sequelae, the three main factors are:

• Chronic anemia
• Ineffective erythropoiesis
• Iron overload

The severity of the condition usually depends on the underlying molecular defects.

Ineffective erythropoiesis happens when the highly unstable alpha chains precipitate in the bone marrow. Within the erythroid precursor, they cause cell death and membrane damage causing ineffective erythropoiesis. There is also hypertrophy of the erythroid marrow in the medullary and extramedullary sites. This is a consequence of ineffective erythropoiesis, which results in skull and face deformities. It could also lead to pathological fractures of long bones and cortical thinning.

The degree of ineffective erythropoiesis is known to be a primary determinant of the development of anemia and the overall reduction in hemoglobin synthesis. The secondary determinant is the peripheral hemolysis of mature RBCs. There is also an increase in gastrointestinal absorption due to chronic anemia, which leads to iron overload. This, in turn, can further cause other serious complications such as endocrine abnormalities, which include hypogonadism and diabetes mellitus. Iron overload may also cause heart failure.

Non-Transfusion-Dependent Thalassemia (NTDT)

Baseline red blood cell phenotypes should be obtained from a patient. Patients should be sent to the thalassemia center once in every 3-6 months to check the following:

• Changes in exercise tolerance
• Shortness of breath
• Complete blood count (CBC)
• Ferritin levels
• Reticulocyte count
• Pain complaints

It is recommended to drink tea with meals and to follow a low-iron diet. The absorption of iron will decrease if zinc levels are also low. In such cases, patients are put on a 1 mg folic acid daily supplementation. Immunizations should also be given to patients with thalassemia intermedia.

Growth and Development

The following should be done for growing children:

• Skull X-rays and Facial Photographs (anterior/lateral and posterior) - Pay attention to the changes in facial bones, especially in younger children and adolescents. Look for any changes in growth velocity. Delayed puberty should be observed and annual dental/orthodontic evaluations should be done. Excessive growth of the head may be seen in patients with mild anemia, which could indicate a need for transfusion therapy. Thus, the patient's head circumference should also be closely monitored.

• Extramedullary Erythropoiesis - One common complication that may arise in non-transfusion-dependent thalassemia patients is tumor masses of the extramedullary erythropoietic tissue. They are often asymptomatic and occur in paraspinal areas. In some cases, there can be an acute neurologic complication and spinal cord compression. The size is often decreased by transfusion therapy. An emergency medical intervention is rarely required.

• Endocrinopathies - Every year, or in every two years, patients should have a DXA scan to assess osteopenia and osteoporosis. Emphasis should be put on bone pain and fractures. Fertility should also be assessed in certain individual cases. Transfusion support should also be considered during pregnancy.

• Cardiopulmonary Assessment - To detect early the left heart decompression adults should do an annual echocardiogram. To detect pulmonary hypertension, tricuspid regurgitation (TR) jet should be done. Annual pulmonary function tests and a six-minute walk test should be done in patients with pulmonary hypertension.

• Transfusion Considerations - The decision for regular transfusions depends on the clinical and laboratory assessment. 

Before starting with long-term blood transfusions, the following indications should be first considered:

• Symptomatic anemia
• Growth failure, poor school performance, and delayed puberty 
• Pulmonary hypertension with or without left heart decompression
• Bone disease or skeletal malformation

During pregnancy or during times of infection, transient transfusions can be considered.

Splenectomy Considerations

Splenectomy can be considered in cases of massive splenomegaly or hypersplenism. Splenectomy can also be done when transfusion is difficult. However, the doctor needs to discuss the complications and benefits of blood transfusions and splenectomy. In patients with thalassemia intermedia, the general recommendations for iron status and endocrine monitoring should be outlined similarly to thalassemia major.

Iron Overload Assessment

Annual monitoring should be done when it comes to iron and ferritin saturation levels. A quantitative assessment of liver iron should be obtained if the iron saturation is more than 60 percent and if the ferritin level is more than 1,000 mg/ml. 

Complications

• Splenectomy and Cholecystectomy - In thalassemia intermedia, a significant enlargement of the spleen is the main indication for splenectomy. There is also a decrease in the patient's hemoglobin level in the absence of other transient factors. In thalassemia intermedia, gallstones are common. Thus, during a splenectomy, the gallbladder should also be inspected. If necessary, cholecystectomy should also be performed.

• Extramedullary Hematopoiesis - Bone marrow activity increases to overcome chronic anemia due to thalassemia intermedia. Primarily, the spleen, lymph nodes, and liver are affected. It may also cause paraplegia and spinal cord compression. This complication can be managed with the help of radiotherapy.

• Leg Ulcers - The skin of the extremities tends to become thin. The subcutaneous tissue also becomes fragile leading to an increased risk of lesions from minimal trauma.

• Thrombophilia - There is a higher risk of developing thrombosis in patients with thalassemia intermedia than those with thalassemia major.

• Pulmonary Hypertension and Congestive Heart Failure - Pulmonary hypertension is considered to be the primary cause of congestive heart failure. Pulmonary hypertension is prevalent in patients with thalassemia intermedia.

• Hepatitis - This condition is less frequent since blood transfusions are less common in thalassemia intermedia cases.

• Endocrine Problems - Endocrine problems such as hypogonadism, diabetes mellitus, and hypothyroidism are quite rare.

• Pregnancy and Infertility - Complications can occur in pregnant women suffering from thalassemia intermedia. However, a spontaneous successful pregnancy is also possible.

• Iron Overload - This condition is triggered by chronic anemia due to an increased intestinal iron absorption. Non-transfusion-dependent thalassemia intermedia patients can be at an increased risk of an iron overload.

Management

• Early initiation of transfusion and iron chelation therapy may be required if there is evidence of growth abnormalities, psychological impact secondary to facial deformities, as well as a poor performance in school.
• A regular follow-up should be done with Doppler ultrasound to check for cardiac complications and initiation of therapy.
• Avoid prolonged immobilization.
• Avoid the use of oral contraceptives.
• Quit smoking.
• Splenectomy can be done, but only when needed.