Thalassemia Intermedia 

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 mostly 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.

The following are histologic images from patients with thalassemia intermedia.

See also Beta Thalassemia, Alpha Thalassemia, Thalassemia, Alpha, Pediatric Thalassemia, Thalassemia Imaging, and Anemia.

In general, because 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; in a case report, a Chinese newborn with β thalassemia major co-inherited Hb H disease (α thalassemia) 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, in a family that 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 red blood cell (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.^{[4, 5]} Hepcidin inhibits iron absorption from the diet and inhibits the recycling of iron by the macrophages. It is increased by iron loading and inhibited by erythropoietic activity.

In patients with thalassemia intermedia who are not 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.^[6]

GDF-15 was investigated as a marker for ineffective erythropoiesis in several anemias including thalassemia intermedia and thalassemia major. The level was the highest in thalassemia major followed by thalassemia intermedia and was significantly lower in other types of anemias. The level was reported to be much higher in splenectomized compared with nonsplenectomized patients, and it correlated well with the severity of the anemia, markers of iron overload, and a predefined clinical severity score.^[7]

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 the effect of hepcidin 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.^[8]

In the future, hepcidin measurements could possibly be used 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.^[9]

In a recent study on mice, a hepcidin agonist was introduced by chemical modifications to avoid the prohibitive expense of natural hepcidin and its unfavorable pharmacologic properties. This product was further modified to increase resistance to proteolysis and oral bioavailability, resulting in a minihepcidin, which has lowered serum iron and liver iron concentration in mice after oral administration. This study brings closer a more effective treatment of iron overload disorders.^[10]

Thalassemia intermedia is inherited and may result from a wide variety of genotypes. Certain homozygous β thalassemia alleles, such as β+ thalassemia in some black individuals or homozygous β0 alleles (δ-β/δ-β) in some patients of Arabic descent, have produced this condition.

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 which can be differentiated by the presence of some hemoglobin (Hb) A.

Heterozygosity for Hb Lepore, a thalassemic hemoglobinopathy, when associated with either β+ or β0 thalassemia can also produce thalassemia intermedia. As noted in Pathophysiology, 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 Pediatric Thalassemia.

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. Internationally, thalassemia intermedia 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 individuals with thalassemia intermedia 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 a hemoglobin (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.

Racial, sexual, and age-related differences in incidence

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.

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.

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.

Patients with milder cases of thalassemia intermedia have a good prognosis; however, after several years of stable disease, many patients develop the severe form of the condition and become transfusion dependent. Patients with the severe forms have the same prognosis as those with thalassemia major.

In most cases, the transformation from the stable state to the transfusion-dependent state is gradual. A patient with a hemoglobin (Hb) of 7-8 g/dL for a long time may drop to a level of 6 g/dL or less. In this case, and in the closely monitored patient, the drop is frequently attributed to a viral infection or transient cause. A single blood transfusion is usually recommended, and the patient is closely monitored. In many occasions, the patient's status continues as before, and no more blood is needed for the time.

However, in other patients, a month or so after the transfusion, the Hb drops again and, at this time, the spleen (which has been enlarged all along) is now larger or more active; therefore, splenectomy is usually considered. Many patients respond well to the procedure and require no more blood for the time being. However, others maintain good Hb for several months or longer before developing the severe anemia again. At this time, the need for regular blood transfusions becomes clear; close monitoring for iron overload followed by chelation therapy when indicated should be undertaken. For this reason, all patients with thalassemia intermedia should be closely monitored in anticipation for developing such changes, which require immediate action.

Morbidity and mortality

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. 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.^[11] This finding is supported by a recent study that identified a hypercoagulable state in patients with thalassemia intermedia.^[12]

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 (see Complications). 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.

Several publications have addressed the issue of hypercoagulability and pulmonary hypertension in patients with thalassemia intermedia, especially those who underwent splenectomy.^[13] This trend continues, 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,^[14] cerebrovascular accidents,^[15] pulmonary hypertension,^[16] Moyamoya disease,^[17] and silent cerebral infarction^[18] are among such reports.

The etiology of the hypercoagulability state is multifactorial,^[19] involving endothelial dysfunction, lack of bioavailability of nitrous oxide (NO),^[14] increased platelet aggregation, and the membrane phospholipid contribution of red blood cells (RBCs).^[20] 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.^[21]

Prevention of thalassemia intermedia is based on public education, family counseling, and widespread measures, such as screening before marriage in high-risk populations, similar to those recommended for thalassemia in general. In fact, education of the population at risk is the most effective prevention method. Measures similar to those undertaken in certain parts of Europe have been very effective in decreasing the numbers of patients with thalassemia in general (see Beta Thalassemia).

Even in developing countries, massive education about thalassemia has changed the outlook and provided local people a great incentive to do whatever is necessary to eliminate the condition or at least minimize its severity. The frequency of voluntary marriage proposal cancellations among at-risk couples in Saudi Arabia, for example, has shown a 5-fold increase from 2004 to 2009 as a result of such intensive education of the population at risk.^[22]