Hemoglobin E/Beta-Thalassemia

Combined
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Diagnosis and reasoning

The infant with anemia is a common problem in primary care - and one which is frequently missed, as these children are often asymptomatic, or manifest only subtle symptoms. In this patient, several clinical findings point towards the presence of anemia: reduced activity, lack of interest, poor feeding, and the presence of pallor upon examination; this is confirmed by the full blood count (FBC). In infants, anemia may be due to one of several etiologies: physiological anemia, poor dietary intake of iron, gastrointestinal blood loss, helminthic infestation, hemoglobinopathy, or hemolytic anemia. His diet appears adequate, and there is no evidence of gastrointestinal hemorrhage. Helminthic infestation of infants is rare in the United States, but should be considered in the developing world, or if there is poor food hygiene. The absence of dysmorphism and the normal length centile make the rare possibility of Fanconi’s Anemia unlikely. In this clinical context, icterus is suggestive of an ongoing hemolysis - but this finding should first be confirmed via investigations. In this patient, the elevated levels of indirect (unconjugated) bilirubin support this presumption. Thus, hemolytic anemias such as G6PD deficiency, pyruvate kinase deficiency, hereditary spherocytosis, and autoimmune hemolytic anemia are a possibility; however, they are clinically less likely in the absence of a positive family history. Hemolysis is also seen in hemoglobinopathies, where there is breakdown of abnormal forms of hemoglobin. In this respect, this child’s ethnicity is an important clue as Thalassemia and HbE disease are commonly seen in parts of Southeast Asia; in addition, the presence of hepatomegaly and splenomegaly is consistent with the extramedullary hematopoiesis seen in Thalassemia. A closer look at his FBC reveals a low mean cell volume (MCV) and mean cell hemoglobin concentration (MCHC); while both Iron Deficiency Anemia (IDA) and Thalassemia can cause these findings, the elevated red blood cell count and normal red cell distribution width (RDW-CV) are more suggestive of the latter. A peripheral blood smear is essential next step; while the hypochromic microcytic cells seen here could potentially be caused by a multitude of diseases (including IDA, anemia of chronic disease, sideroblastic anemia and lead poisoning), the presence of target cells and tear drop cells makes thalassemia the most likely. Iron studies are also important in the investigation of microcytic anemia; a low serum iron level, together with a low ferritin level and a low transferrin saturation is consistent with the Iron Deficiency Anemia( IDA), while a low or borderline serum iron, with high ferritin and transferrin saturation makes anemia of chronic disease likely. However, in this patient, iron studies do not reveal any abnormality, effectively ruling out both of the above diagnoses. As thalassemia is the probable diagnosis, the next step should be High Performance Liquid Chromatography (HPLC) for identification and quantification of abnormal hemoglobin; the high levels of HbE and HbF seen here indicate the presence of Hemoglobin E/Beta Thalassemia major disease. The presence of severe anemia with an Hb of 5.4g/dl in this patient mandates urgent blood transfusion; iron chelation therapy is also important as these patients are prone to develop iron overload over time. As might be obvious, iron therapy should be avoided. Splenectomy should be considered if there is hypersplenism causing increased red cell destruction, or if there is risk of rupture of an enlarged spleen; in this patient, it is probably not indicated right now.


Discussion

HbE is an abnormal hemoglobin with a single point mutation at position 26 of the gene that codes for the beta chain in hemoglobin. Individuals who are heterozygous (HbE trait) or homozygous (HbEE) for the disease are usually asymptomatic. Beta Thalassemia occurs as a result of a point mutation of the gene that codes for the beta hemoglobin chain on chromosome 11. In some patients the mutation allows for production of some beta chains - known as Beta+ thalassemia; the more severe-Beta0 form results in complete absence of beta chains. In both instances there is precipitation of the excess alpha chains; delta chains present in the blood mop up excess alpha chains forming HbA2; gamma chains also perform a similar role, forming HbF. In patients in whom HbE is combined with Beta thalassemia or HbS disease, severe symptoms occur; overall, HbE/Beta Thalassemia the most serious of the HbE syndromes commonly seen in South East Asia, with the prevalence increasing in North America due to migration. In some parts of Thailand, Laos and Cambodia the prevalence of the HbE mutation is as high as 60 percent. The resistance of HbE to invasion by Plasmodium falciparum is thought to be the cause. In the infant and toddler age group, common symptoms include lethargy, developmental delay, lack of activity, poor appetite and pica. Extramedullary hematopoiesis due to severe anemia results in hepatomegaly and splenomegaly; as the child grows older, frontal bossing becomes apparent. Differentiation of HbE/Beta thalassemia from pure Beta thalassemia is of prognostic importance, due to the higher morbidity and mortality. The most serious form is HbE/Beta0 Thalassemia while the heterozygous HbE/ Beta+ Thalassemia can have a wide variation in phenotype ranging from mild to transfusion dependent anemia. The International Committee for Standardization in Hematology (ICSH) Expert Panel on abnormal hemoglobins and Thalassemias recommends a Full Blood Count (FBC), Hemoglobin electrophoresis, tests for solubility and sickling, and quantification of HbA2 and HbF, when investigating these patients. Note that while electrophoresis has been used for many years, HPLC is emerging as the method of choice for quantification of HbA2 and HbF, and for identification of Hb variants. After identification of a thalassemia syndrome, DNA testing may be necessary, especially for genetic counselling. Both Southern blot and PCR techniques are used for this purpose. Treatment involves optimizing the Hb level to enhance the level of functioning. This is usually done via repeated blood transfusions. Maintaining the Hb at 9.5g/dl has been shown to result in a reduced transfusion requirement and improved control of iron stores. Transfusion Transmitted Infections (TTI) are a possibility among the multi-transfused. Hepatitis B, Hepatitis C and Human Immunodeficiency Virus (HIV) are the most commonly seen TTI’s. Iron overload is a problem in both transfused and non transfused patients. In the non-transfused, this is due to the excess precipitation of alpha chains and increased gastrointestinal absorption. Iron overload can cause a slate-grey complexion, cardiomyopathy, heart failure, cirrhosis, hypothyroidism, diabetes, and growth failure due to iron deposition in endocrine organs. There are several methods to evaluate the degree of iron overload. A commonly used method is serum ferritin; other options include liver iron levels by analysis of a biopsy, superconducting quantum interference device (SQUID), and magnetic resonance imaging (MRI). Serum ferritin is considered a poor marker as the level may change in inflammation, infection, ascorbate level or on the intensity of transfusion therapy. Liver iron is considered the gold standard, with a level higher than 15 mg/dl predicting a higher risk of cardiac disease and death. The objective of iron chelation is to maintain iron at a safe level, while preventing cardiac, hepatic and endocrine complications of overload. Deferoxamine should be started when serum ferritin is above 1000 mg/dl; it can be administered subcutaneously, intravenously or intramuscularly. Common side effects are reduced visual acuity, deafness and growth retardation. Poor compliance is a common problem as patients require chelation sessions lasting up to 8 hours, 5 to 7 days a week. Oral chelators such as Deferiprone and Deferasirox have been introduced as alternatives to encourage better compliance. These can be combined with Deferoxamine for more effective chelation. Splenectomy is recommended in individuals in whom annual transfusions exceed 200 mL packed cells/kg; this usually significantly reduces the transfusion requirements and iron accumulation. Such patients should receive pneumococcal and meningococcal vaccination at least two weeks prior to the procedure. Note that while transfusion and chelation therapy improves survival in thalassemia patients, they are not curative; hemopoietic stem cell transplantation is the only cure currently available. Individuals identified with the HbE or beta thalassemia trait should undergo genetic counselling after detailed genetic testing. In high prevalence areas such as South East Asia and the Mediterranean, there is public health advocacy for mandatory testing before marriage.


Take home messages

  1. Anemia in infants may present with very subtle features; a high degree of suspicion is essential for early diagnosis.
  2. HbE is common among persons of South East Asian ethnicity.
  3. HPLC is the method of choice for identification and quantification of abnormal hemoglobin subtypes.
  4. Both transfused and non-transfused patients with thalassemia are at risk of iron overload.

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