eMedicine Specialties > Pediatrics: General Medicine > Hematology

Thalassemia Intermedia

Author: Hassan M Yaish, MD, Professor of Pediatrics, University of Utah School of Medicine; Director of Hematology Services, Medical Director, Mountain States Hemophilia and Thrombophilia Treatment Center; Pediatric Hematologist/Oncologist, Department of Pediatrics, Primary Children's Medical Center
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Updated: Sep 29, 2009

Introduction

Background

Thalassemia intermedia is a term used to define a group of patients with β thalassemia in whom the clinical severity of the disease is somewhere between the mild symptoms of the β thalassemia trait and the severe manifestations of β thalassemia major. The diagnosis is a clinical one that is based on the patient maintaining a satisfactory hemoglobin (Hb) level of at least 6-7 g/dL at the time of diagnosis without the need for regular blood transfusions.

This initial definition of thalassemia intermedia, which was based on clinical observation alone, retained its validity even after some of the specific mutations associated with thalassemia intermedia were recognized because severity of the clinical course remains unpredictable even in known genotypes. For this reason, some patients with a β thalassemia intermedia genotype are treated as if they have thalassemia major because they present with severe manifestations; similarly, others with a thalassemia intermedia genotype are considered to have thalassemia minor because of the mild or even asymptomatic nature of their condition. This variability is most likely related to the presence or absence of modifying genes. It has been surprisingly seen among siblings with the same genotype.

Because of the significant overlap in clinical severity among the 3 types of β thalassemia and despite the fact that several genotypes are associated with the β thalassemia intermedia picture, the diagnosis continues to be a clinical one, regardless of the genotype involved. Moreover, in an individual patient, the diagnosis may change from thalassemia intermedia to thalassemia major once the patient begins to have more severe symptoms and to require regular blood transfusions.

Pathophysiology

Because, in general, all symptoms and manifestations of thalassemia are caused by an imbalance in globin chain synthesis, the milder symptoms of thalassemia intermedia in any one patient may be attributable to the following:

• The particular inherited globin chain mutations (ie, milder homozygous or combined heterozygous mutations affecting the β globin promoter) may produce these milder symptoms.
• Co-inheritance of a genetic determinant that decreases the imbalance between α and β chain production (eg, α thalassemia trait) can occur. A Chinese newborn with β thalassemia major co-inherited Hb H disease and, as a result, had a β thalassemia intermedia phenotype.¹
• γ chain production may be increased, resulting in an elevated level of Hb F, as in the case of β/δ deletion mutations that, when associated with a β thalassemia gene mutation, produce a combined heterozygous condition that can result in thalassemia intermedia. For example, a family was reported with homozygosity for a rare β (0) thalassemia; the children developed thalassemia intermedia phenotype and not the expected severe form of thalassemia major. When the mutations were studied, they were linked to the (G) γ -globin (xmnI) and (A) γ -globin promotor, resulting in production of Hb F.²
• Most patients with Hb E/β thalassemia (interaction of Hb E and β thalassemia) exhibit the clinical course of thalassemia intermedia. The incidence of this condition is increasing in the United States because of the large population of new immigrants to the United States from Southeast Asia.
• In contrast, some of the complex genetic interactions may instead result in a more severe phenotype than expected.³

The symptoms of thalassemia intermedia reflect ineffective erythropoiesis, which leads to anemia, medullary expansion, and extramedullary hematopoiesis. Iron overload is a potential complication of thalassemia, even in patients who do not require RBC transfusions. It results from excessive absorption of dietary iron, mediated by the downregulation of hepcidin, which is a hepatic hormone that acts as a major regulator of systemic iron homeostasis. Hepcidin inhibits iron absorption from the diet and inhibits the recycling of iron by the macrophages. It is increased by iron loading and is inhibited by erythropoietic activity.

In patients with thalassemia intermedia who are receiving regular blood transfusions, the erythropoietic activity is exaggerated. This usually results in inhibition of hepcidin, which causes increased absorption of iron from the diet and depletion of iron macrophages. Iron overload is supposed to increase the hepcidin level, thus, suppressing the absorption of iron. However, this does not occur in patients with thalassemia because, in β thalassemia, a serum factor produced by the bone marrow, known as growth differentiation factor 15 (GDF 15), may override the potential effect of iron overload on the expression of the hepcidin gene (HAMP), thus removing the protection of hepcidin against iron absorption. This provides an explanation for the failure to arrest the excessive iron absorption in such patients.⁴

In contrast, hepcidin levels are usually elevated in patients with thalassemia major who are receiving regular blood transfusions because of reduced erythropoietic activities and increased iron overload. As a result of hepcidin's effect on iron recycling by macrophages, ferritin levels are usually high in patients with β thalassemia major receiving blood transfusions compared with those with thalassemia intermedia who are not receiving transfusions despite similar liver iron concentrations in both conditions.⁵

Hepcidin measurements could possibly be used in the future as diagnostic tool for iron overload in patients with thalassemia, and hepcidin may even be used as a therapeutic agent for some iron overload conditions.⁶

Frequency

United States

Because of the recent immigration waves from Eastern Europe and Southeast Asia, more patients with thalassemia are expected to be encountered in the United States.

International

This condition appears to be much more common in the Mediterranean basin, northern Africa, the Indian subcontinent, and Eastern Europe than in other areas of the world. One reason for the higher incidence of thalassemia intermedia in developing countries is that medical resources for aggressive management of symptomatic thalassemia are unavailable. Most affected individuals in these regions remain untreated.

Many likely die from complications of the disease; other individuals, who have milder courses and, by definition, are considered to have thalassemia intermedia because they are able to maintain an Hb level of more than 6-7 g/dL, survive with chronic disease. If these individuals lived in a developed country, they would be diagnosed with thalassemia major and would be treated. For this reason, similar to the situation in the United States, no accurate figures for the worldwide incidence of β thalassemia intermedia are currently available.

Mortality/Morbidity

Morbidity is fairly common in thalassemia intermedia because many patients are not transfused regularly despite their marginal Hb level. The obligatory increase in erythropoiesis results in bone deformities, osteoporosis, fractures, growth retardation, tumorlike masses with possible spinal cord compression, neurologic complications, as well as thrombotic events. Additional morbidity comes from iron overload, which eventually occurs even in patients who do not receive blood transfusions. The ferritin level is usually lower in thalassemia intermedia compared with the level encountered in thalassemia major, despite the similar iron overload degree.

Mortality rates are usually high in developing countries because of complications such as organ failure, severe anemia and its sequelae, infections, and (unchelated) iron overload. Heart disease is the leading cause of mortality associated with this condition. It results from the high output state caused by chronic tissue hypoxia as well as the vascular involvement that leads to pulmonary vascular resistance.

In recent years, several publications have addressed the issue of hypercoagulability and pulmonary hypertension in patients with thalassemia intermedia, especially those who underwent splenectomy.⁷ This trend is continuing, with a large number of reports describing several clinical presentations, all of which point to an underlying thrombotic event as a cause of the clinical complications.

Pulmonary emboli,⁸ cerebrovascular accidents,⁹ pulmonary hypertension,¹⁰ Moyamoya disease,¹¹ and silent cerebral infarction¹² are among such reports. The etiology of the hypercoagulability state is multifactorial,¹³ involving endothelial dysfunction, lack of bioavailability of nitrous oxide (NO),⁸ increased platelet aggregation, and RBCs membrane phospholipid contribution.¹⁴ However, the major role of splenectomy in thalassemia intermedia should not be underestimated. The hypercoagulability state that is somewhat striking in thalassemia intermedia is not limited to this condition; it is also reported in sickle cell disease.¹⁵

A multicenter study to assess the incidence of thrombotic events in patients with thalassemia found that 4% of patients with thalassemia intermedia develop thrombotic events compared with only 0.9% with thalassemia major.¹⁶

Race

As with all thalassemia syndromes, the condition is encountered in people of all races. However, thalassemia intermedia is more common among certain racial groups in the United States, such as persons of Mediterranean, Asian, or African descent.

Sex

Thalassemia intermedia occurs with equal frequency in males and females. Menstruating females are, on average, somewhat more anemic and marginally less likely to develop iron overload.

Age

Unlike thalassemia major, which usually becomes evident during the first year of life, the onset of thalassemia intermedia is typically somewhat later because of its milder clinical picture. In some cases, the diagnosis is made by chance when a hematologic abnormality is found incidentally.

Clinical

History

The history in thalassemia intermedia usually depends on the patient's age at diagnosis and the severity of the condition at onset.

• Patients with mild cases show no significant symptoms and may go undiagnosed.
• In moderately severe cases, patients or their family members may observe slight pallor, slight yellowish discoloration of the sclerae, or enlarged abdomen. Low hemoglobin (Hb) levels or an enlarged spleen upon routine physical examination may represent the first indication of the disease.
• In more severe forms, the patient may seek medical advice because of malaise, pallor, easy fatigability, or bone deformities or fractures.
• In extremely rare circumstances, a patient with anemia and an enlarged abdomen may develop a serious unexpected symptom, such as paralysis.
  • This usually reflects transverse myelopathy that results from compression of the spinal cord by a tumorlike mass of extramedullary hematopoietic tissue.
  • In such patients, detailed workup reveals the correct diagnosis.
• The patient might seek medical advice because of a family history of thalassemia or the knowledge that both parents are carriers of a thalassemic condition.

Physical

The physical examination findings vary according to severity and stage of the disease.

• Pallor is almost always present to some degree.
• Abnormal facies with prominent facial bones and dental malocclusions are observed in patients with severe disease who are untreated. Growth retardation, failure to thrive, fractures, and bone deformities are also commonly found in this group of patients.
• An enlarged spleen is a common finding.
• Younger patients who are seen early may show only minimal findings upon examination, such as pallor or splenomegaly.

Causes

• The condition is inherited and may result from a wide variety of genotypes. Certain homozygous β thalassemia alleles, such as β+ thalassemia in some African Americans or homozygous β0 alleles (δ-β/δ-β) in some patients of Arabic descent, have produced thalassemia intermedia.
• Several forms of combined heterozygous thalassemia can also result in a clinical course consistent with thalassemia intermedia. Two examples are β0/(δ-β)0 thalassemia, described in Greeks, Italians, and Asians, and the β+/(δ-β)0 variant, which is clinically similar to the first condition but can be differentiated by the presence of some Hb A.
• Heterozygosity for Hb Lepore, a thalassemic hemoglobinopathy, when associated with either β+ or β0 thalassemia can also produce thalassemia intermedia. As previously noted, the interaction of β thalassemia with Hb E disease produces thalassemia intermedia in many patients.
• More than 150 different mutations in the β thalassemia genes are currently known. For more detailed information, see Thalassemia.

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