Thalassemia Intermedia Clinical Presentation

Updated: Dec 24, 2018
  • Author: May C Chien, MD; Chief Editor: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP  more...
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Presentation

Clinical Manifestations

Beta thalassemia intermedia refers to beta thalassemia with non–transfusion-dependent anemia. Characterized by a less-severe phenotype than beta thalassemia major, the condition nonetheless has a wide range of clinical presentations. The presentation of beta thalassemia intermedia tends to occur later than that of beta thalassemia major, often in the third or fourth decade of life. [2, 1]

Beta thalassemia does not present in infants aged less than six months, because gamma-globulin synthesis predominates over beta-globulin synthesis in this age group.

Despite maintaining a level of hemoglobin sufficient for tissue oxygenation, patients with thalassemia can develop a range of complications due to longstanding hemolytic anemia and ineffective erythropoiesis, including jaundice, splenomegaly, bone deformities, osteoporosis, fractures, growth retardation, extramedullary hematopoietic pseudotumors, [3]  pulmonary hypertension, thromboembolism, [4] iron overload, and skin ulcers.

Anemia

Patients tend to have a moderate level of anemia that is not transfusion dependent. By convention, this generally corresponds to a hemoglobin of 7-7.5 g/dL.  However, transfusions are often required episodically during periods of stress, such as infection or pregnancy. Patients can develop transfusion dependency in later adulthood.

Jaundice

Patients can have jaundice from chronic hemolytic anemia. Bilirubin gallstones can result in cholelithiasis.

Splenomegaly

Most patients have a palpable spleen, a consequence of chronic hemolysis and extramedullary hematopoiesis. [1]

Extramedullary hematopoietic pseudotumors

Extramedullary hematopoiesis can occur in almost any region of the body to compensate for ineffective red cell production by the bone marrow. Affected areas include the spleen, liver, lymph nodes, thymus, heart, breasts, prostate, kidneys, adrenal glands, pleura, skin, and spinal canal. [1, 5] Paraspinal involvement can have debilitating clinical consequences due to spinal cord compression. [6]  

Bone deformities and disease

Changes described in thalassemia major, such as frontal bossing, cortical thinning, dilation of the medullary cavities, prominence of the zygomatic bones, and shortening of the long bones, can also be seen in patients with thalassemia intermedia. In addition, many patients have osteoporosis, likely from a combination of endocrine dysfunction, 25-hydroxy vitamin D deficiency, and bone marrow expansion. Pathologic fractures, especially in long bones and vertebrae, can result.

Thromboembolic disease

Thalassemia intermedia is associated with a hypercoagulable state. [1] 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% of individuals with thalassemia major. [7]  The etiology of the hypercoagulability state is multifactorial, [8]  involving endothelial dysfunction, [9]  lack of bioavailability of nitrous oxide (NO), [10]  increased platelet aggregation, and the membrane phospholipid contribution of red blood cells. [11]

Pulmonary hypertension

Although the cause is not entirely clear, pulmonary hypertension likely develops from longstanding chronic anemia, hypoxia, iron overload, and microthrombotic disease of the pulmonary circulation. It is the leading cause of right-sided heart failure in patients with thalassemia major. 

Skin ulcers

Older thalassemia intermedia patients can develop leg ulcers, as oxygen reduction causes subcutaneous tissue to thin.

Iron overload

Iron overload is a potential complication of thalassemia, even in patients who do not require red blood cell 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. [12, 13]  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.