pa tho physiology of beta thalassemia

Pathophysiology of beta thalassemiaAuthorStanley L Schrier, MD Section EditorsStanley L Schrier, MDDonald H Mahoney, Jr, MD Deputy EditorsStephen A Landaw, MD, PhDMelanie S Kim, MD

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INTRODUCTION DEFINITIONS Beta (0) thalassemia Beta (+) thalassemia Beta thalassemia major Beta thalassemia minor Beta thalassemia intermedia Anemia Protection against severe malaria Yersinia infection HEMOLYTIC ANEMIA Oxidant injury Non-transferrin bound iron Material properties of thalassemic RBC RBC deformability Reduced membrane deformability Membrane instability Membrane protein abnormalities Red blood cell dehydration Increased destruction by macrophages HYPERCOAGULABLE STATE INEFFECTIVE ERYTHROPOIESIS Abnormal erythrokinetics Morphologic changes in RBC precursors Altered assembly of membrane proteins Apoptosis of red cell precursors DISEASE HETEROGENEITY IN HEMOGLOBIN E/BETA THALASSEMIA SUMMARY AND LESSONS FROM MURINE MODEL OF BETA THALASSEMIA REFERENCES

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ALGORITHMS Red cell transporters FIGURES Globin gene clusters Dense RBCs in beta thalassemia PICTURES

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Beta thalassemia intermedia

INTRODUCTION The major hemoglobin in adults is hemoglobin A, which is a tetramer consisting of two pairs of globin polypeptide chains: one pair of alpha chains; and one pair of beta chains. In normal subjects, globin chain synthesis is very tightly controlled so that the ratio of production of alpha to non-alpha chains is 1.00 0.05. There are two copies of the alpha globin gene on chromosome 16. A single beta globin gene resides on chromosome 11 adjacent to genes encoding the beta-like globin chains, delta and gamma (figure 1). (See "Structure and function of normal human hemoglobins".) Thalassemia refers to a spectrum of diseases characterized by reduced or absent production of one or more globin chains. Beta thalassemia is due to impaired production of beta globin chains, which leads to a relative excess of alpha globin chains. These excess alpha globin chains are unstable, incapable of forming soluble tetramers on their own, and precipitate within the cell, leading to a variety of clinical manifestations. The degree of alpha globin chain excess determines the severity of subsequent clinical manifestations, which are profound in patients homozygous for impaired beta globin synthesis and much less pronounced in heterozygotes who generally have minimal or mild anemia and no symptoms. (See "Clinical manifestations and diagnosis of the thalassemias".) Alpha thalassemia, in comparison, is due to impaired production of alpha globin chains, which leads to a relative excess of beta globin chains. (See "Pathophysiology of alpha thalassemia".) The toxicity of the excess beta globin chains in alpha thalassemia on the red cell membrane skeleton appears to be less than that of the excess partially oxidized alpha globin chains in beta thalassemia [1]. This probably explains why the clinical manifestations are generally less severe in alpha compared with beta thalassemia of comparable genetic severity (except for homozygous alpha (0) thalassemia, which is incompatible with extrauterine life, leading to hydrops fetalis and/or death shortly after delivery). The pathophysiology of the anemia in beta thalassemia will be reviewed here. This discussion will focus on the mechanisms by which unbalanced alpha globin chain synthesis leads to hemolysis of red cells in the peripheral circulation and, more importantly, to the extensive destruction of erythroid precursors within the bone marrow and in extramedullary sites, such as the liver and spleen (ineffective erythropoiesis). The molecular pathology of the thalassemias is discussed separately.

(See "Molecular pathology of the thalassemic syndromes".)

INTRODUCTION The deficiencies in hemoglobin biosynthesis that characterize the various forms of thalassemia arise from mutations in or near the two globin gene clusters which encode

the globin polypeptide subunits of hemoglobin. To date, no forms of thalassemia arising primarily from defects in iron or heme metabolism have been described. All known forms are due to inherited defects in the biosynthesis or post-translational stability of the globin subunits themselves. Because of their small size, their arrangement into relatively compact gene clusters, and their well characterized physiology, pathology, and clinical genetics, the globin genes were the first human genes to be cloned and thoroughly characterized. The mutations that cause the thalassemia syndromes were the first to be defined at the level of their DNA structure. Indeed, the delineation of the impact of these mutations on mRNA and protein expression provided the paradigm for the identification of mutations causing other diseases. The molecular pathology of the thalassemic syndromes will be discussed here. This subject is best understood from the perspective of the normal structure and function of the genes encoding the individual globins [1]. The first section of this review will outline the essential features of normal hemoglobin biosynthesis and its underlying molecular biology. (See "Principles of molecular genetics" and "Structure and function of normal human hemoglobins".) The second section will discuss illustrative examples of the over 100 different mutations causing thalassemia and explain their effects on globin synthesis. The pathophysiologic and clinical aspects of the thalassemic syndromes are discussed separately. (See "Pathophysiology of alpha thalassemia" and "Pathophysiology of beta thalassemia" and "Clinical manifestations and diagnosis of the thalassemias".)

Beta Thalassemiay y y y y y y y

What are the thalassemias? What is beta thalassemia? What is the difference between thalassemia minor and major? What is Mediterranean anemia? What is the genetic pattern of inheritance of beta thalassemia? The diagnosis of thalassemia major and minor The treatment of thalassemia major Find a local Hematologist in your town

What are the thalassemias?

The thalassemias are a group of genetic (inherited) blood disorders that share in common one feature, the defective production of hemoglobin, the protein that enables red blood cells to carry oxygen (and carbon dioxide). There are many different disorders with defective hemoglobin synthesis and, hence, many types of thalassemia. What is beta thalassemia? The most familiar type of thalassemia is beta thalassemia. It involves decreased production of normal adult hemoglobin (Hb A), the predominant type of hemoglobin

from soon after birth until death. (All hemoglobin consists of two parts: heme and globin). The globin part of Hb A has 4 protein sections called polypeptide chains. Two of these chains are identical and are designated the alpha chains. The other two chains are also identical to one another but differ from the alpha chains and are termed the beta chains. In persons with beta thalassemia, there is reduced or absent production of beta globin chains. What is the difference between thalassemia minor and major? There are two forms of beta thalassemia. They are thalassemia minor and thalassemia major (which is also called Cooley's anemia). Thalassemia minor: The individual with thalassemia minor has only one copy of the beta thalassemia gene (together with one perfectly normal beta-chain gene). The person is said to be heterozygous for beta thalassemia. Persons with thalassemia minor have (at most) mild anemia (with slight lowering of the hemoglobin level in the blood). This situation can very closely resemble that with mild iron-deficiency anemia. However, persons with thalassemia minor have a normal blood iron level (unless they have are iron deficient for other reasons). No treatment is necessary for thalassemia minor. In particular, iron is neither necessary nor advised. Thalassemia major (Cooley's anemia): The child born with thalassemia major has two genes for beta thalassemia and no normal beta-chain gene. The child is homozygous for beta thalassemia. This causes a striking deficiency in beta chain production and in the production of Hb A. Thalassemia major is, therefore, a serious disease. The clinical picture associated with thalassemia major was first described in 1925 by the American pediatrician Thomas Cooley. Hence, the name Cooley's anemia in his honor. At birth the baby with thalassemia major seems entirely normal. This is because the predominant hemoglobin at birth is still fetal hemoglobin (Hb F). Hb F has two alpha chains (like Hb A) and two gamma chains (unlike Hb A). It has no beta chains so the baby is protected at birth from the effects of thalassemia major. Anemia begins to develop within the first months after birth. It becomes progressively more and more severe. The infant fails to thrive (to grow normally) and often has problems feeding (due to easy fatigue from lack of oxygen, with the profound anemia), bouts of fever (due to infections to which the severe anemia predisposes the child) and diarrhea and other intestinal problems.

Thalassemia MedlinePlus Topics Thalassemia Images

Thalassemia major

Thalassemia minor

Read More AnemiaEndocrine glands Hemoglobin

Thalassemia is a blood disorder passed down through families (inherited) in which the body makes an abnormal form of hemoglobin, the protein in red blood cells that carries oxygen. The disorder results in excessive destruction of red blood cells, which leads to anemia. See also:y y

Hemolytic anemia Sickle cell disease

Causes

Hemoglobin is made of two proteins: Alpha globin and beta globin. Thalassemia occurs when there is a defect in a gene that helps control production of one of these proteins. There are two main types of thalassemia:y y

Alpha thalassemia occurs when a gene or genes related to the alpha globin protein are missing or changed (mutated). Beta thalassemia occurs when similar gene defects affect production of the beta globin protein.

Alpha thalassemias occur most commonly in persons from southeast Asia, the Middle East, China, and in those of African descent. Beta thalassemias occur in persons of Mediterranean origin, and to a lesser extent, Chinese, other Asians, and African Americans. There are many forms of thalassemia. Each type has many different subtypes. Both alpha and beta thalassemia include the following two forms:y y

Thalassemia major Thalassemia minor

You must inherit the defective gene from both parents to develop thalassemia major. Thalassemia minor occurs if you receive the defective gene from only one parent. Persons with this form of the disorder are carriers of the disease and usually do not have symptoms. Beta thalassemia major is also called Cooley's anemia. Risk factors for thalassemia include: y y

Asian, Chinese, Mediterranean, or African American ethnicity amily history of the disorder

Symptoms

The most severe form of alpha thalassemia major causes stillbirth (death of the unborn baby during birth or the late stages of pregnancy). Children born with thalessemia major (Cooley's anemia) are normal at birth, but develop severe anemia during the first year of life. Other symptoms can include:y y y y y

Bone deformities in the face atigue Growth failure Shortness of breath Yellow skin (jaundice)

Persons with the minor form of alpha and beta thalassemia have small red blood cells (which are identified by looking at their red blood cells under a microscope), but no symptoms.Exams and Tests

A physical exam may reveal a swollen (enlarged) spleen. A blood sample will be taken and sent to a laboratory for examination.

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Red blood cells will appear small and abnormally shaped when looked at under a microscope. A complete blood count (CBC) reveals anemia. A test called hemoglobin electrophoresis shows the presence of an abnormal form of hemoglobin.

A test called mutational analysis can help detect alpha thalassemia that cannot be seen with hemoglobin electrophoresis.Treatment

Treatment for thalassemia major often involves regular blood transfusions and folate supplements. If you receive blood transfusions, you should not take iron supplements. Doing so can cause a high amount of iron to build up in the body, which can be harmful. Persons who receive significant numbers of blood transfusions need a treatment called chelation therapy to remove excess iron from the body. Bone marrow transplant may help treat the disease in some patients, especially children.Outlook (Prognosis)

Severe thalassemia can cause early death due to heart failure a, usually between ages 20 and 30. Frequent blood transfusions with therapy to remove iron from the body helps improve the outcome. Less severe forms of thalassemia usually do not result in a shorter life span.Possible Complications

Untreated, thalassemia major leads to heart failure and liver problems, and makes a person more likely to develop infections. Blood transfusions can help control some symptoms, but may result in too much iron which can damage the heart, liver, and endocrine system.When to Contact a Medical Professional

Call for an appointment with your health care provider if:y y

You or your child has symptoms of thalassemia You are being treated for the disorder and new symptoms develop

Prevention

Genetic counseling and prenatal screening may be available to those with a family history of this condition who are planning to have children.

Alternative Names

Mediterranean anemia; Cooley's anemia; Beta thalassemia; Alpha thalassemiaont Size

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What are the thalassemias? What is beta thalassemia? What is the difference between thalassemia minor and major? What is Mediterranean anemia? What is the genetic pattern of inheritance of beta thalassemia? The diagnosis of thalassemia major and minor The treatment of thalassemia major Beta Thalassemia Glossary Beta Thalassemia Index Find a local Hematologist in your town

What is Mediterranean anemia? The gene for beta thalassemia is not evenly distributed among peoples. It is, for example, relatively more frequent in people of Italian and Greek origin, both of which

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Beta Thalassemia Index Glossary ind a Local Doctor

Beta Thalassemia (cont.)

are peoples from the Mediterranean. Because of this, thalassemia major has been called Mediterranean anemia. The name thalassemia was coined at the University of Rochester in upstate New York by the Nobel Prize-winning pathologist George Whipple and the professor of pediatrics William Bradford from the Greek thalassa for sea and -emia, meaning the blood. Thalassemia means "sea in the blood." But for the Greeks, the sea was the Mediterranean, so thalassemia also conveys the idea of the Mediterrranean in the blood. The reason that the gene for beta thalassemia is relatively common, for example, among people of Italian and Greek origin is that parts of Italy and Greece were once full of malaria. The presence of thalassemia minor (like sickle cell trait in Africa) afforded protection against malaria, and therefore, this gene thrived. What is the genetic pattern of inheritance of beta thalassemia? The pattern of genetic transmission of beta thalassemia (and sickle cell disease) was deciphered by James V. Neel when he was at the University of Rochester (he later went to Michigan). Dr. Neel recognized that the parents of children with thalassemia major had thalassemia minor with one beta thalassemia gene. When these parents had children, they have a 25% chance of having a thalassemia major child (with both genes for beta thalassemia), a 50% chance of having children with thalassemia minor (with only one gene for beta thalassemia), and a 25% chance of having a child without thalassemia major or minor (with both genes for normal beta chains). This form of inheritance is medically referred to as an autosomal recessive pattern.Font Size A A Ay y y y y y

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Beta Thalassemia Index Glossary Find a Local Doctor

Beta Thalassemia (cont.)In this Articley y y y y y y y y y


What is Mediterranean anemia? The gene for beta thalassemia is not evenly distributed among peoples. It is, for example, relatively more frequent in people of Italian and Greek origin, both of which are peoples from the Mediterranean. Because of this, thalassemia major has been called Mediterranean anemia. The name thalassemia was coined at the University of Rochester in upstate New York by the Nobel Prize-winning pathologist George Whipple and the professor of pediatrics William Bradford from the Greek thalassa for sea and -emia, meaning the blood. Thalassemia means "sea in the blood." But for the Greeks, the sea was the Mediterranean, so thalassemia also conveys the idea of the Mediterrranean in the blood. The reason that the gene for beta thalassemia is relatively common, for example, among people of Italian and Greek origin is that parts of Italy and Greece were once full of malaria. The presence of thalassemia minor (like sickle cell trait in Africa) afforded protection against malaria, and therefore, this gene thrived. What is the genetic pattern of inheritance of beta thalassemia? The pattern of genetic transmission of beta thalassemia (and sickle cell disease) was deciphered by James V. Neel when he was at the University of Rochester (he later went to Michigan). Dr. Neel recognized that the parents of children with thalassemia major had thalassemia minor with one beta thalassemia gene. When these parents had children, they have a 25% chance of having a thalassemia major child (with both genes for beta thalassemia), a 50% chance of having children with thalassemia minor (with only one gene for beta thalassemia), and a 25% chance of having a child without thalassemia major or minor (with both genes for normal beta chains). This form of inheritance is medically referred to as an autosomal recessive pattern.



The diagnosis of thalassemia major and minor Persons with thalassemias have smaller sized red blood cells than normals as well as low red blood cell counts (anemia). Thalassemia major and thalassemia minor can now be diagnosed (and distinguished from one another) not only by conventional clinical and blood testing, but also by molecular medical tests. These tests permit accurate diagnosis to be made at any time, even before birth (in fact, well before the beta chain machinery is fired up to make beta chains for hemoglobin). The treatment of thalassemia major Infants with thalassemia major are well at birth because of a special form of hemoglobin present in the fetus and newborn. Eventually, however, this hemoglobin is replaced by defective hemoglobin. Symptoms emerge late in the first year of life. The child develops pale skin, irritability, growth retardation, swelling of the abdomen due to enlargement of the liver and spleen (hepatosplenomegaly) with jaundice. This is associated with severe anemia with rupture of the red blood cells (hemolytic anemia). The child with thalassemia major becomes dependent on blood transfusions and, although they do help, they create further problems including iron overload. Folic acid supplementation is often given. At this time, there is only treatment for relieving the symptoms of the illness for thalassemia major. Gene therapy remains a potential treatment for the future. The long-term hope is that thalassemia major will be cured by insertion of the normal beta-chain gene through gene therapy or by another modality of molecular medicine.Beta Thalassemia At A Glancey y y y

Thalassemias are inherited blood disorders. Thalassemia patients make defective hemoglobin. There are two forms of beta thalassemia: thalassemia minor and thalassemia major (also called Cooley's anemia). Beta thalassemia is more frequent in people of Italian and Greek origin.



The diagnosis of thalassemia major and minor Persons with thalassemias have smaller sized red blood cells than normals as well as low red blood cell counts (anemia). Thalassemia major and thalassemia minor can now be diagnosed (and distinguished from one another) not only by conventional clinical and blood testing, but also by molecular medical tests. These tests permit accurate diagnosis to be made at any time, even before birth (in fact, well before the beta chain machinery is fired up to make beta chains for hemoglobin). The treatment of thalassemia major Infants with thalassemia major are well at birth because of a special form of hemoglobin present in the fetus and newborn. Eventually, however, this hemoglobin is replaced by defective hemoglobin. Symptoms emerge late in the first year of life. The child develops pale skin, irritability, growth retardation, swelling of the abdomen due to enlargement of the liver and spleen (hepatosplenomegaly) with jaundice. This is associated with severe anemia with rupture of the red blood cells (hemolytic anemia). The child with thalassemia major becomes dependent on blood transfusions and, although they do help, they create further problems including iron overload. Folic acid supplementation is often given. At this time, there is only treatment for relieving the symptoms of the illness for thalassemia major. Gene therapy remains a potential treatment for the future. The long-term hope is that thalassemia major will be cured by insertion of the normal beta-chain gene through gene therapy or by another modality of molecular medicine.Beta Thalassemia At A Glancey y y y

Thalassemias are inherited blood disorders. Thalassemia patients make defective hemoglobin. There are two forms of beta thalassemia: thalassemia minor and thalassemia major (also called Cooley's anemia). Beta thalassemia is more frequent in people of Italian and Greek origin.

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Hemoglobin Index Glossary

HemoglobinMedical Author: Siamak Nabili, MD, MPH Medical Editor: William C. Shiel, Jr., MD, FACP, FACRy y y y y y y y

What is hemoglobin? How is hemoglobin measured? What are normal hemoglobin values? What does a low hemoglobin level mean? What does a high hemoglobin level mean? What is sickle cell disease? What is thalassemia? Patient Discussions: Hemoglobin - Helped With Your Diagnosis

What is hemoglobin?

Hemoglobin is the protein molecule in red blood cells that carries oxygen from the lungs to the body's tissues and returns carbon dioxide from the tissues to the lungs. Hemoglobin is made up of four protein molecules (globulin chains) that are connected together. The normal adult hemoglobin (Hbg) molecule contains 2 alpha-globulin chains and 2 beta-globulin chains. In fetuses and infants, there are only a few beta chains and the hemoglobin molecule is made up of 2 alpha chains and 2 gamma

chains. As the infant grows, the gamma chains are gradually replaced by beta chains. Each globulin chain contains an important central structure called the heme molecule. Embedded within the heme molecule is iron that transports the oxygen and carbon dioxide in our blood. The iron contained in hemoglobin is also responsible for the red color of blood. Hemoglobin also plays an important role in maintaining the shape of the red blood cells. Abnormal hemoglobin structure can, therefore, disrupt the shape of red blood cells and impede its function and its flow through blood vessels.

Hemoglobin (cont.)In this Articley y y y y y y y y

What is hemoglobin? How is hemoglobin measured? What are normal hemoglobin values? What does a low hemoglobin level mean? What does a high hemoglobin level mean? What is sickle cell disease? What is thalassemia? Patient Discussions: Hemoglobin - Helped With Your Diagnosis Hemoglobin Index

How is hemoglobin measured?

Hemoglobin is usually measured as a part of the complete blood count (CBC) from a blood sample. Several methods exist for measuring hemoglobin, most of which are done currently by automated machines designed to perform several different tests on blood. Within the machine, the red blood cells are broken down to get the hemoglobin into a solution. The free hemoglobin is exposed to a chemical containing cyanide which binds tightly with the hemoglobin molecule to form cyanmethemoglobin. By shining a light through the solution and measuring how much light is absorbed (specifically at a wavelength of 540 nanometers), the amount of hemoglobin can be determined.What are normal hemoglobin values?

The hemoglobin level is expressed as the amount of hemoglobin in grams (gm) per deciliter (dl) of whole blood, a deciliter being 100 milliliters. The normal ranges for hemoglobin depend on the age and, beginning in adolescence, the gender of the person. The normal ranges are:y y y y y y y y

Newborns: 17-22 gm/dl One (1) week of age: 15-20 gm/dl One (1) month of age: 11-15gm/dl Children: 11-13 gm/dl Adult males: 14-18 gm/dl Adult women: 12-16 gm/dl Men after middle age: 12.4-14.9 gm/dl Women after middle age: 11.7-13.8 gm/dl

All of these values may vary slightly between laboratories. Some laboratories do not differentiate between adult and "after middle age" hemoglobin values.What does a low hemoglobin level mean?

A low hemoglobin is referred to as anemia. There are many reasons for anemia. Some of the more common causes are:y y y

loss of blood (traumatic injury, surgery, bleeding colon cancer or stomach ulcer), nutritional deficiency (iron, vitamin B12, folate), bone marrow problems (replacement of bone marrow by cancer,

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suppression by chemotherapy drugs, kidney failure), and abnormal hemoglobin (sickle cell anemia). Previous 1 2 3 4 5 Next

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What does a high hemoglobin level mean?

Higher than normal hemoglobin levels can be seen in people living at high altitudes and in people who smoker. Dehydration produces a falsely high hemoglobin which disappears when proper fluid balance is restored. Some other infrequent causes are:y y

advanced lung disease (for example, emphysema), certain tumors,

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a disorder of the bone marrow known as polycythemia rubra vera, and abuse of the drug erythropoietin (Epogen) by athletes for blood doping purposes.

What is sickle cell disease?

Sickle cell disease is a genetic condition in which the quality of hemoglobin is defective. This condition can cause abnormal hemoglobin which, in turn, can result in abnormally shaped (sickled) red blood cells. These abnormal red blood cells cannot easily pass through small blood vessels and, therefore, could deprive the body organs of adequate oxygen. Sickle cells also have a shorter life span than normal red blood cells (10-20 days compared to 120 days). This rapid turn over may result in inadequate time to replace the red blood cells and may result in anemia. In order for a person to have sickle cell anemia, one defective hemoglobin gene must be inherited from each parent. If only one gene is inherited from one parent, then the conditions is much milder and it is referred to as sickle cell trait.

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What is thalassemia?

Thalassemia refers to a group of hereditary conditions with quantitative hemoglobin deficiency. The body's failure to make globulin molecules will lead to compensatory mechanism to make other less compatible globulin molecules. The severity of these conditions depend on the type of deficient globulin chain and the severity of the underproduction. Mild disease may be only present as mild anemia, whereas, severe deficiency may not be compatible with life.

pa tho physiology of beta thalassemia

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