Hemoglobin is made of iron (heme) and protein (globin). The function of hemoglobin is to carry oxygen from the lung to tissues. There are three main types of normal hemoglobin found in adults: Hemoglobin A, Hemoglobin A2, and Hemoglobin F. The types of globin molecule combinations, namely alpha, beta, gamma or delta, determine the type of hemoglobin. All of the normal hemoglobin is a combination of alpha and non-alpha chains. The gene for alpha globin is located on chromosome 16. Hemoglobin A is composed of one pair of alpha globin chains and one pair of beta globin chains. It makes 95% to 98% of adult hemoglobin. Hemoglobin A2 is a pair of alpha chains and a pair of delta chains. It makes 1% to 3% of adult hemoglobin. Hemoglobin F is comprised of two alpha and two gamma chains. It makes up for the majority of neonatal hemoglobin but in normal adults is 2% to 3% of the total hemoglobin. The percentages fluctuate based on age, genetics, medications, and underlying conditions.
Thalassemias are a group of disorders caused by abnormal production of globin chains. The production can be diminished or can be absent for one or more of the globin chains. This imbalance of globin chain production impairs production of normal hemoglobin. This impairment causes ineffective erythropoiesis with intramedullary hemolysis. Alpha thalassemia refers specifically to the abnormal or absent manufacturing of alpha globin chains. These are associated with more than 15 different genetic mutations. The severity of the clinical condition is based on the mutation type. The severity of mutation is based on which of the two alpha globin loci is affected. Mutations can also be deletion or non-deletion. In deletion mutation, there is an inheritance of a single alpha globin gene. With the non-deletion type, a patient has inherited two alpha globin genes, but one gene carries a non-deletion abnormality, for example, point mutation. In non-deletion, the severity of clinical expression is also affected by if the mutation partially or fully blocks the production of the remaining normal alpha chains. Hemoglobin H disease occurs when only one normal alpha gene has been inherited. One of these most common non-deletion subtypes of Hemoglobin H is called Hemoglobin Constant Spring. HbH disease tends to be more severe in patients with the non-deletion-type likely due to interference with transcription of the normal alpha chain gene by the abnormal one.
Hemoglobin H forms when only one normal alpha gene has been inherited. This causes significantly impaired alpha globin production. In the neonatal period, this will cause an excess of gamma, and in adults, this leaves an excess of beta globin chains. Free alpha chains are insoluble. Both gamma and beta chains are soluble and make homotetramers. Hemoglobin H is made of four beta chains, and HbBarts is made of four gamma chains. They are however unstable, and some precipitate within the cell, leading to a variety of clinical manifestations. HbH in adults can make up to 40% of circulating hemoglobin in affected individuals. This hemoglobin is more susceptible to oxidant injury and has poor oxygen carrying capacity. Its affinity is ten times more than HbA. It has an abnormal oxyhemoglobin dissociation curve. This means that it can bind to oxygen, but does not deliver it to tissues normally.
Alpha thalassemia traits are thought to be protective against malaria, and in populations with high incidences of malaria, the trait can be found in up to 90% of the population. Hemoglobin H is similar and found mostly in warm climates. The populations with highest incidences are found in Southeast Asia, the Mediterranean, and the Middle East. Hemoglobin Constant Spring is the most common form of non-deletion alpha thalassemia. One percent to 2% of individuals living in northeastern Thailand, 5% to 8% of individuals in southern China, and one-quarter of women in an ethnic minority population in Vietnam are found to have Hemoglobin Constant Spring.
Hemoglobin H can cause chronic hypochromic microcytic anemia and hemolytic anemia which can worsen in periods of oxidant stress. This can be effectively broken down as ineffective erythropoiesis and increased hemolysis. The microcytic hypochromic anemia is due to impaired hemoglobin production due to decreased alpha chain synthesis and hyperhydration of the cell. The cause of the hyperhydration in alpha thalassemia is not clear. One theory argues that the K-Cl cotransporter stops early, thereby preventing the usual loss of K-Cl and water that is part of the red blood cell remodeling process.
Hemoglobin H has also shown shortened survival down to half of normal, 12 to 19 days versus normal of 28 to 37 days. This has accounted for two main factors: abnormal red blood cell membrane with increased rigidity and increased inclusion bodies. The inclusions were thought to be aggregates of beta chain tetramers which precipitate in the red blood cell and cause damage, leading to their removal by the spleen. These inclusion bodies are also proposed to cause the increased susceptibility to oxidant stress.
HbH disease is classified as moderate to severe in alpha thalassemia. Due to the variety of genetic mutations as explained previously, there is marked variation in phenotypic expression. Patients can be asymptomatic, have episodic anemia requiring transfusions, and even fatal hydrops fetalis in utero.
Clinical presentation usually starts in the latter part of gestation with a hemolytic anemia due to the formation of HbBarts. The most severe form will result in fatal hydrops fetalis. At birth, neonates present with jaundice and anemia.
As they age, patients will have fluctuating degrees of anemia. This anemia is due to a combination of ineffective erythropoiesis and hemolysis. Periods of increased oxidant stress such as sepsis or certain medications tend to increase the rate of hemolysis. Patients would then have the typical presentation of hemolytic anemia, indirect hyperbilirubinemia, elevated LDH, decreased haptoglobin, splenomegaly, hepatomegaly, jaundice, variable bony changes, premature biliary tract disease, leg ulcers, and eventually iron overload if multiple transfusions are required without adequate iron chelation.
In adults, the diagnosis is suspected in patients with a microcytic anemia with normal iron stores and a normal hemoglobin A2 level on electrophoresis. Hemoglobin levels are usually 8 to 10 g/dL at baseline.
The peripheral blood film in HbH disease shows hypochromia and microcytosis with inclusion bodies. Inclusion bodies are better visualized with a supravital dye such as methyl violet or brilliant cresyl blue. Bone marrow demonstrates erythroid hyperplasia with poorly hemoglobinized erythroblasts carrying inclusion bodies. Hemoglobin electrophoretic or chromatographic techniques can demonstrate HbH. DNA-based genotyping is required for precise diagnosis and is important in prenatal testing and genetic counseling.
Supplementation with folic acid should be given because there is hemolytic anemia. HbH patients are at risk of clinical manifestations with oxidative damage. Blood counts should be monitored, and transfusional intervention may be required during periods of oxidant stress, such as infection or oxidant drug use. Patients must be monitored carefully for complications of chronic transfusion and given iron chelation support as needed, especially during the second and third decades of life. Patients require careful genetic counseling.
The most important differential diagnosis of all the thalassemic syndromes is iron deficiency, which should always be ruled out. Beta thalassemia and combinations of sickle cell disease and thalassemia should also be ruled out.
Patientes with HbH disease should be followed regularly by a hematologist experienced in the care of hemoglobinopathies and iron overload.
Genetic counselling is mandatory for young patients willing to conceive. Patients should be educated about the consequences of iron overload and the importance of adherence to treatment.
The management of alpha thalassemia is ideally done by a multidisciplinary team that consists of a hematologist, internist, primary care provider, geneticist, nurse, pharmacist, and a dietitian. This hemoglobinopathy can affect multiple organs and close monitoring is required. Supplementation with folic acid should be given because there is hemolytic anemia. HbH patients are at risk of clinical manifestations with oxidative damage. Blood counts should be monitored, and transfusional intervention may be required during periods of oxidant stress, such as infection or use of oxidant drugs. Patients must be monitored carefully for complications of chronic transfusion and given iron chelation support as needed, especially during the second and third decades of life. Patients require careful genetic counseling.
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