What is Thalassemia? A Comprehensive Overview
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Thalassemia – a type of anemia
Anemia is defined as a decrease in Red Blood Cells (RBCs) counts below normal. Any significant decrease in RBCs, its essential components—hemoglobin or hematocrit—or any combination of these values fall under anemia. The reason for decreased hemoglobin or hematocrit does not matter, whether through iron deficiency, lead poisoning, thalassemia, kidney failure, cancer, or even something as straightforward as blood loss. As a result, common symptoms are weakness and tiredness, or can even be as serious as shortness of breath or loss of consciousness. Identifying the specific mechanism causing the anemia aids in the treatment of restoring the RBCs levels back to normal. Thalassemia is a type of anemia where the hemoglobin molecule becomes dysfunctional, usually through genetic mutations, producing unhealthy hemoglobin and lowering the effective hemoglobin count in the body. Most cases of thalassemia are most commonly found in Mediterranean, Arab, North African, and Southeast Asian populations. [1][2][3][4]
An Overview of Hemoglobin
Hemoglobin is an essential component of RBCs, with their primary function to carry oxygen from the lungs to the cells so it can breathe and make energy. When genetic mutations (such as with Thalassemia) produce unhealthy hemoglobin, the resultant altered RBCs cannot carry oxygen as efficiently, depriving the cells of necessary oxygen and decreasing energy. [1][2][3][4]
Adult hemoglobin protein (HgA) is composed of 4 protein subunits, 2 alpha-globins and 2 beta-globins. Each subunit houses 1 heme molecule and 1 positively charged iron atom, which are used to attract and hold onto the negatively charged oxygen for oxygen transport throughout the body. Fetal hemoglobin (HgF) is instead composed of 2 alpha-globins and 2 gamma-globins and is expressly used by the fetus during pregnancy and through the first six months after birth. [2][3][4]
Mutations in genes that create either the alpha- or beta-globins interfere with healthy hemoglobin production. With these mutations, the protein structure of hemoglobin changes, making the RBCs smaller (microcytic), less colorful (hypochromic), and more prone to premature death (hemolysis), which are all indicators of a decreased capacity of the hemoglobin to carry oxygen. These different hemoglobin structures are given different names based on the mutation, such as Hemoglobin E (HbE) to differentiate it from normal adult hemoglobin (HbA). Different thalassemias are categorized by how different gene mutations affect subunit and hemoglobin production, and can broadly be classified into thalassemias involving alpha- or beta-globin mutations. [2][3][4][5][6]
What is Alpha-Thalassemia?
Alpha-thalassemia is caused by synthesis defects with the alpha-globin of hemoglobin. The human body has 2 genes that control alpha-globin synthesis, and each gene has 2 copies called alleles, totaling 4 alleles. Symptoms begin when 1 or more of those 4 alleles become dysfunctional, with symptom severity increasing with each allele absence. The four magnitudes of disease presentation for are as follows:
Alpha-thalassemia minima, with 1 dysfunctional allele
Alpha-thalassemia minor, with 2 dysfunctional alleles
Hemoglobin H (HbH) disease (also: alpha-thalassemia intermedia), with 3 dysfunctional alleles
Hemoglobin Bart’s hydrops fetalis syndrome (also: alpha-thalassemia major), with all 4 dysfunctional alleles
Alpha-Thalassemia Minima and Minor
Those with alpha-thalassemia minima are asymptomatic, with maybe some slight deviations from normal RBC size and function. People may go their entire lives not knowing they have alpha-thalassemia minima. Those with alpha-thalassemia minor begin presenting with mild anemia, with normal RBC size and count more deviated than not; however, it normally does not require interventional medical treatment. Regardless, to avoid medical intervention, maintaining a healthy diet and avoiding infection keeps anemia to a minimum. [2][3][4][5]
Hemoglobin H Disease: Alpha-Thalassemia Intermedia
With 3 dysfunctional alleles, alpha-globin production plummets. The deficient alpha-globins and excess beta-globins cause hemoglobin proteins to compensate by using 4 beta-globins instead. This new variant of hemoglobin is called Hemoglobin H (HbH) and is the namesake for alpha-thalassemia intermedia. With 10-40% of the HbA replaced by HbH, HbH disease causes mild-to-moderate anemia. HbH is significantly less effective than normal HbA, and cannot properly deliver oxygen to the cells. Alongside significant microcytic and hypochromatic blood cells, HbH disease causes excess beta-globins to circulate and clog up the bloodstream, leading to complications such as enlarged spleen, heart issues, gallstones, jaundice, lower leg ulcers, and folic acid deficiency in serious cases. However, in most instances, counteracting the anemia with folate supplements to help restore proper hemoglobin production makes treatment relatively straightforward. Transfusions are only necessary during anemic crises, such as during serious viral infections or oxidative drug intake. Thankfully, HbH is much rarer than alpha-thalassemia minima and minor, considering it needs 3 different mutations in 3 different alleles to fully manifest. [2][3][4][5]
Hemoglobin Bart's Hydrops Fetalis Syndrome: Alpha-Thalassemia Major
Hemoglobin Bart’s hydrops fetalis syndrome (or Hb Bart’s syndrome), the rarest of all alpha-thalassemias, develops when all 4 alleles that control alpha-globin creation are dysfunctional or absent. Hb Bart’s is generally considered the most serious and dangerous alpha-thalassemia, as it replaces the fetal hemoglobin (HbF) that fetuses and infants under 6 months solely rely on during development. With essentially zero alpha-globins available, HbF cannot form; a highly unstable configuration of 4 gamma-globins form instead, and is dubbed Hemoglobin Bart’s (Hb Bart’s). 80-90% of all HbF in the fetus is replaced with Hb Bart’s, causing severe hemolytic anemia (early RBC death) in utero and after birth. Most RBCs never fully develop, with cells only getting 10-20% of oxygen they need, which is fatal when left untreated. With this chronic anemia from constant RBC cell death, regular blood transfusions are required both in utero and after birth to replenish the lost hemoglobin, as the body does not make nearly enough. In order to gain independence from from lifelong transfusions, a stem cell transplant is required to provide new non-mutated DNA that properly produces alpha-globins. [2][3][4][5]
What is Beta-Thalassemia?
Beta-thalassemia results from beta-globin synthesis defects. While there is only 1 gene that controls beta-subunit synthesis, there are over 200 identified disease-causing mutations within that gene, with symptoms depending on the severity of the mutation (partial dysfunction or complete dysfunction) and with duplicity (if 1 or 2 alleles are affected). Beta-thalassemia is much more common than alpha-thalassemia and can be broadly divided into three magnitudes: minor, major, and intermedia. [2][3][4][6]
Beta-Thalassemia Minor
Beta-thalassemia minor results in mild anemia from microcytic and hypochromic cells. In contrast with HbH disease, beta-thalassemia minor has alpha-globin excess and beta-globin deficiency, reducing the total amount of healthy HbA available for use. Treatment does not normally require blood transfusions; supporting primarily with folic acid supplements are considered for severe cases of beta-thalassemia minor. [2][3][4][6]
Beta-Thalassemia Major
Beta-thalassemia major results in severe hemolytic anemia, with essentially nonexistent beta-globins and abundantly excess alpha-globins making HbA and RBCs much more microcytic, hypochromic, and prone to self-destruction. There is also an observed excess in gamma-globins. As such, the excess alpha- and gamma-globins combine and make HbF, replacing 70–90% of all HbA and contributing to the body’s ineffective oxygen transport. Furthermore, the presence of excess alpha-globins is significantly more toxic and detrimental to the body compared to excess beta-globins, and can seriously disrupt spleen, heart, gallbladder, and bone marrow function. Thus, enlarged spleens, heart issues, gallstone production, jaundice, lower leg ulcers, and folic acid deficiency also appear. Similarly to Hb Bart’s disease, constant and life-long blood transfusions are required to control symptoms, with the best treatment being stem cell transplants to replenish the body’s ability to produce beta-globins. By restoring the balance between the alpha- and beta-globins, the body can make enough HbA to fully support the body’s oxygen requirements. [2][3][4][6][7][8]
Beta-Thalassemia Intermedia
Beta-thalassemia intermedia is defined as anything in between minor and major. Considering the hundreds of possible mutations, beta-thalassemia intermedia broadly encompasses a wide range of symptoms ranging from mild to moderate to severe, necessitating individualized treatment. Anemic symptom onset can begin anytime between childhood and adulthood and chronically persists. Since stem cell transplants are usually reserved for cases of beta-thalassemia major, treating moderate-to-severe beta-thalassemia intermedia requires regular blood transfusions and leading to intermedia-specific complications. Similar to how imbalances between alpha- and beta-globins cause dysfunction, imbalances between hemoglobin levels and iron levels create additional dysfunction. Frequent blood transfusions increases the risk of iron overload (the opposite of iron deficiency) overwhelming different organ systems, requiring counteractive iron chelation treatments to restore normal iron levels. Additionally, beta-thalassemia intermedia is observed to negatively affect the bone marrow more than in major. As such, secondary symptoms like spleen enlargement and gallstone production are more severe in beta-thalassemia intermedia, often prompting surgical removal of the spleen or gallbladder to manage symptoms in lieu of a stem cell transplant. [2][3][4][6][7][8][9][10][11]
Beta-Hemoglobin Variants: Sickle Cell Anemia, Hemoglobin C, Hemoglobin D, Hemoglobin E
Hemoglobin S: Sickle Cell Anemia
Some beta-globin gene mutations are so prevalent in their population that they are given their own name. The most common and most dangerous named mutation in beta-globins produces Hemoglobin S (HbS), more well-known as sickle cell anemia. As the first identified and named beat-globin mutation, most cases exist in sub-Saharan African populations. With this HbS beta-globin mutation, the resulting RBCs become sickle-shaped, resulting in severe hemolytic anemia. Thankfully, if only one allele mutates to HbS, about 35-40% of HbA is replaced by HbS, and sickle cell symptoms do not manifest. However, with two HbS alleles, 55-90% of HbA is replaced with HbS, leading to pain and organ crises alongside chronic hemolytic anemia, which require regular transfusions, pain medications, or even stem cell transplants in extreme cases. Additionally, with the identification of more alleles, different combinations of alleles produce different symptoms. Combinations of HbS and nonspecific beta-thalassemia mutations, for example, can produce a variety of sickle cell anemia symptoms (depending on the severity of the aggregate beta-globin dysfunction). [1][3][4][6][12][13]
Hemoglobin C
The second-named beta-globin mutation is named Hemoglobin C (HbC), commonly found in populations in Atlantic West Africa, South East Asia, South and Central America, and Southern Europe. Similar to HbS, those with only one HbC allele mutation experience very mild symptoms, if any, with 50% of the HbA replaced with HbC. Those with two HbC allele mutations experience Hemoglobin C disease, with mild-to-moderate symptoms of hemolytic anemia and spleen enlargement. Combinations of HbC and HbS have been observed that produce moderate sickle cell anemia symptoms. [2][3][4][6][12][14]
Hemoglobin D
Hemoglobin D (HbD) is the third named common beta-globin mutation. Those with one HbD allele similarly experience no symptoms, and those with two HbD alleles have Hemoglobin D disease, describing mild hemolytic, microcytic, and hypochromic anemia, with variable cases of mild-to-moderate spleen enlargement. One HbD combined with one HbS or other general beta-thalassemia also present with hemolytic anemia to varying degrees. HbD is also the first variant subdivided by subpopulations. For example, while Punjab populations and populations in Los Angeles both have HbD occurrences, their clinical expression is distinct from one another. As such, those subvariations were subbed HbD-Punjab and HbD-Los Angeles respectively. [2][3][4][6][12][15]
Hemoglobin E
The fourth named beta-globin mutation is Hemoglobin E (HbE), and is most common in Southeast Asian populations, particularly Thailand and Laos. Those with one HbE allele experience mild symptoms with mild hypochromic anemia similar to beta-thalassemia minor, with only 20-35% of HbA replaced by HbE. Those with two HbE alleles have microcytic hypochromic anemia similar to mild beta-thalassemia intermedia, with 95% of HbA replaced by HbE. Because of HbE’s detrimental interactions with other thalassemia traits, HbE is considered the second-most dangerous of the common beta-thalassemia mutations. An HbE allele in conjunction with another nonspecific beta-thalassemia mutation can cause anything between mild beta-thalassemia intermedia to beta-thalassemia major. In rare cases, an HbE allele can combine with HbH disease and to create HbAE Bart’s disease, which produces a mild-to-moderate thalassemia intermedia. Two HbE alleles and HbH disease combining produces HbEF Bart’s, an more moderate-to-severe thalassemia with 80% HbE, 10% HbF, 10% Hb Bart’s, and 0% HbA. Because of HbE’s versatile nature, disease-specific treatments are indicated. [2][3][4][6][16]
Conclusion
Most people who have Thalassemia are asymptomatic, and may not even know they have it. Of those cases, even fewer know what it does to them. However, if left unchecked, two asymptomatic parents may find their child suffering from major thalassemias. Genetic counseling may be advised for those looking to become parents if both parents are suspected to have thalassemia. Additionally, those with symptomatic diseases have many options to improve symptoms and reduce complications when managed by their primary care physician or hematologist. With future medical advancements, gene therapy (physically altering genes to remove mutations and restore original function) may become viable treatment options as well, and can hopefully become the standard for curing thalassemia and removing one modality of anemia. [1][2][17]
References
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