Thalassemia refers to a set of genetic disorders characterized by mutations in the hemoglobin gene. This impairs the function and number of red blood cells, ultimately causing anemia. There are two primary types of thalassemia: alpha thalassemia and beta thalassemia, both of which can have minor or major versions.
Now, let’s quickly review the physiology of red blood cells and hemoglobin. Red blood cells, or RBCs are small, round cells that are responsible for delivering oxygen and removing carbon dioxide throughout the body. They are produced in the bone marrow, in a process called erythropoiesis; then, they move around the blood for about 120 days and finally, they are destroyed by the spleen, in a process called hemolysis.
Now, inside each RBC, there are millions of hemoglobin molecules. Hemoglobin is a compound protein made up of heme and globin. Specifically, adult hemoglobin is made up of four globin chains, two alpha and two beta, and each of these proteins contains a heme group in the middle.
Heme is a ring-shaped structure, and it’s the home of one iron ion that can attach to oxygen. So at the end of the day, it’s hemoglobin that makes it possible for RBCs to perform their main role, which is oxygen transport. Finally, when red blood cells are destroyed, the heme is further broken down in the liver into bilirubin, which is subsequently excreted, while the iron is stored in the liver for future use.
Now, thalassemias are caused by an inherited DNA mutation in the genes that code for the hemoglobin alpha or beta subunits. So, clients at higher risk of thalassemia include those with a positive family history; as well as people from ethnic groups with a higher prevalence of thalassemia, like those originating from the area around the Mediterranean sea, the Middle East, India, Pakistan and Africa. Now, pathology-wise, thalassemia starts with a genetic mutation in the genes for the alpha or beta globins, that’s inherited in an autosomal recessive pattern. This causes reduced synthesis of the corresponding globin, if only one gene is mutated, or absent synthesis, if both genes are mutated. The first scenario causes thalassemia minor, while the later causes thalassemia major.
What is more, when alpha globin chains are affected, alpha thalassemia develops, and when beta globin chains are affected, that causes beta thalassemia.
So far so good. Now, with reduced or absent globin production, the resulting hemoglobin molecule is abnormal. As a consequence, abnormal RBCs are also produced in the bone marrow, and some of them are destroyed before they even make it into the circulation. This is called ineffective erythropoiesis, and it’s one thing that makes RBC levels low in thalassemia. The other factor is that mature RBCs that do make it into the circulation are also destroyed more quickly by the spleen, so there’s increased hemolysis. As a consequence, anemia develops, because there aren’t enough RBCs to deliver oxygen to all the tissues in the body.
As a compensatory mechanism, the bone marrow can increase RBC production, and it becomes packed with immature RBC precursors, which cause bone marrow hyperplasia.
Additionally, the body can increase RBC production in extramedullary sites, so in places other than the bone marrow, such as the liver. This makes the liver enlarge, causing hepatomegaly. However, these new red blood cells are frequently fragile and immature, so they’re also destroyed quickly by the spleen. All this overwork can also make the spleen enlarge, which is called splenomegaly.
Additionally, increased breakdown of RBCs causes increased breakdown of hemoglobin. This leads to a buildup of bilirubin in the blood, which causes jaundice. Excess bilirubin can also deposit and condense in the gallbladder, causing cholelithiasis, which is really just a fancy term for gallstones. Finally, iron overload, or hemochromatosis, either from excessive RBC breakdown or from transfusions done to treat the anemia, can also make iron pile up in different organs, affecting their function.
For example, when iron accumulates in the heart, it can cause cardiomyopathy, arrhythmias, hypertension, or cardiac failure. Iron overload can also contribute to osteoporosis; peripheral neuropathy; and affect endocrine glands like the thyroid, causing hypothyroidism; or the pancreas, causing diabetes mellitus. Alright, now let’s translate that into a clinical picture of thalassemia. Thalassemia minor is typically asymptomatic, while in thalassemia major, signs and symptoms may appear in children by age two.
Manifestations often include general weakness, fatigue, slow growth, pale skin or jaundice, as well as dark urine. The characteristic appearance in children is a prominent forehead, which is called frontal bossing, along with wide-set eyes, a flat nose, and maxillary prominence. Clinical assessment can reveal hepatomegaly, splenomegaly, or both.
Clinical manifestations of complications can include fractures, in case of osteoporosis; diminished sensitivity in case of peripheral neuropathy; as well as weight gain, fatigue and hair and skin changes with hypothyroidism, or polyuria, polydipsia, polyphagia and weight loss with diabetes mellitus.
The diagnosis of thalassemia starts with the client’s history and medical assessment. Blood tests typically include a complete blood count or CBC which often shows low hemoglobin and low mean corpuscular volume, which translates as microcytic anemia. A peripheral blood smear can also show microcytic and hypochromic red blood cells. Iron studies are done to rule out iron deficiency anemia, as well as check for iron overload; and hemoglobin electrophoresis can be done for DNA analysis to confirm a genetic mutation. Of note, for a baby at risk for thalassemia, genetic testing of the amniotic fluid can diagnose the condition before birth.
Treatment is typically only required for thalassemia major, and includes frequent blood transfusions, to correct the anemia, followed by chelation therapy with medications like desferrioxamine or deferasirox, to remove the excess iron from the blood transfusions. In children with severe symptoms, a stem cell transplant can be done to eliminate the need for frequent transfusions.
Surgery can also help! For example, a cholecystectomy can be done in clients with cholelithiasis, and a splenectomy may be necessary for clients with a very enlarged spleen. Bear in mind, though, that after a splenectomy, a client is at higher risk of developing infections, especially with bacteria like Streptococcus pneumoniae or Neisseria meningitidis.
Finally, gene therapy or genome editing is an emerging treatment that could be utilized to alter the blood stem cell genes to produce normal globin, but more research is needed in the field.