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Thalassemia: Causes, Symptoms, Diagnosis

Written by Ana Aleksic, MSc (Pharmacy) | Last updated:
Jonathan Ritter
Puya Yazdi
Medically reviewed by
Jonathan Ritter, PharmD, PhD (Pharmacology), Puya Yazdi, MD | Written by Ana Aleksic, MSc (Pharmacy) | Last updated:

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Thalassemias are a group of inherited diseases that affect red blood cells. Their symptoms vary in severity. Some people live a normal life, while others need life-long blood transfusions. Read on to learn more about how thalassemia is inherited and how lifestyle changes and genetic counseling can impact health.

What Is Thalassemia?

Definition

Thalassemias are genetic disorders caused by over 300 known mutations in the hemoglobin genes. Hemoglobin is a protein found in red blood cells that carry oxygen in the blood. Hemoglobin is composed of an iron-containing group (heme group) and protein subunits (globin) [1, 2].

Types of Hemoglobin

Before birth, fetal hemoglobin is the main oxygen-carrying component in the blood. After birth, it gradually converts to adult hemoglobin. The types of hemoglobin found in the blood are [3]:

  • Adult hemoglobin: 2 alpha and 2 beta subunits (97% of hemoglobin)
  • Hemoglobin alpha 2: 2 alpha and 2 delta subunits (2.5% of hemoglobin)
  • Fetal hemoglobin: contains 2 alpha and 2 gamma subunits (0.5% of hemoglobin)

Thalassemia mutations produce defective or missing alpha, beta, or delta chains of the hemoglobin. As a result, hemoglobin levels are lower and there are fewer healthy red blood cells. Because they have fewer healthy blood cells, people with thalassemia often have mild to severe anemia [4].

Causes & Types of Thalassemia

Causes

Common causes of thalassemia are outlined below. Work with your doctor or other health care professional for an accurate diagnosis.

Thalassemias are caused by changes or deletions in the hemoglobin genes. Everyone inherits 2 copies of each gene, one from each parent [5, 6].

Severe forms of thalassemia occur when a person inherits multiple defective copies. Men and women are at equal risk of inheriting it, meaning the genes that affect thalassemia are on non-sex chromosomes (autosomal disease) [5, 6].

The following genes affect hemoglobin subunits [1, 7]:

  • Alpha – HBA1 and HBA2, found on chromosome 16
  • Beta – HBB, found on chromosome 11
  • Delta – HBD, found on chromosome 11
  • Gamma – HBG1 and HBG2, found on chromosome 11

Alpha-Thalassemia Conditions

Defective or reduced production of the alpha subunits results in alpha-thalassemia. All hemoglobin contains 2 alpha subunits. Evidence suggests that the genes associated with the alpha subunits are HBA1 and HBA2, mutations in which are associated with the following conditions [6]:

Hemoglobin Bart Syndrome

  • Characterized by a loss of all 4 alpha subunit gene copies
  • Caused by deletions on both copies of HBA1 and both copies of HBA2
  • Usually results in death before birth
  • Pregnant women carrying a fetus with this syndrome may experience exacerbated anemia, preeclampsia, congestive heart failure, and miscarriage.

Hemoglobin H Disease

  • Characterized by a loss of 3 alpha subunit gene copies
  • Caused by deletion of both copies of the HBA1 or HBA2 gene and also either deletion or inactivation of 1 copy of the other gene
  • Can also be caused by the Constant Spring variant (HBA2 gene) which produces inactive alpha subunits that are abnormally long and unstable

Alpha-Thalassemia Trait

  • Characterized by a loss of 2 alpha subunit gene copies
  • Can be caused by deletion or inactivation of 2 alpha subunit genes or by inactive variants of both copies of the HBA2 gene
  • People with alpha-thalassemia trait may have moderate symptoms

Alpha-Thalassemia Silent Carrier

  • Characterized by a loss of 1 alpha subunit gene copy, due to deletion or inactivation
  • People with this condition usually have no symptoms

Beta-Thalassemia Conditions

Reduced production of the beta subunit and thus reduced adult hemoglobin levels in the blood can cause beta-thalassemia. Depending on the type of mutation, beta-thalassemia is typically classified as [5, 1]:

Beta-Thalassemia Major

  • Also known as Cooley’s Anemia and Mediterranean Anemia
  • Characterized by hemoglobin levels below 7 g/dL
  • People with beta-thalassemia major require regular blood transfusions.

Beta-Thalassemia Intermedia

  • Characterized by hemoglobin levels between 7-10 g/dL
  • People with beta-thalassemia intermedia may require blood transfusions at some point(s) in their life.

Beta-Thalassemia Minor

  • Characterized by below-average hemoglobin and red blood cell size.
  • Generally, people with beta-thalassemia minor do not have severe symptoms

Hemoglobin E is a common, abnormally structured variant of beta hemoglobin, which is produced at reduced levels and by itself, has similar symptoms to beta-thalassemia minor. However, it can also occur simultaneously with alpha- or beta-thalassemias. The types of hemoglobin E thalassemias are [8, 9]:

Hemoglobin E/Beta-Thalassemia

  • This condition accounts for approximately 50% of severe beta-thalassemias.
  • It occurs when the structural variant (hemoglobin E) from one parent is inherited with a beta-thalassemia gene from the other parent.
  • Many different factors affect the severity of this condition, such as the type of beta-thalassemia.

Hemoglobin AE/Bart’s Disease

  • Characterized by the inheritance of hemoglobin H disease (3 defective copies of alpha subunit genes) with 1 copy of the hemoglobin E variant
  • Considered an intermediate thalassemia disorder

Hemoglobin EF/Bart’s Disease

  • Characterized by the inheritance of hemoglobin H disease (3 defective copies of alpha subunit genes) with either hemoglobin E/beta-thalassemia or both copies of the hemoglobin E variant
  • Considered an intermediate thalassemia disorder
  • Its symptoms are similar to hemoglobin H disease

Delta-Thalassemia Conditions

Delta-thalassemia is a very rare mutation in the delta subunit gene (HBD gene). Since the hemoglobin-containing delta subunits only make up 2.5% of total hemoglobin, mutations in this gene are not severe. However, delta-thalassemia can occur with beta-thalassemia [10, 11, 12]:

Delta/Beta-Thalassemia

  • Results from the deletion of both the delta and beta subunit genes on chromosome 11
  • Production of gamma subunits increases, which means increased levels of fetal hemoglobin, which can decrease symptom severity
  • Deletion of one copy of delta and one copy of beta subunits is symptomatically similar to beta-thalassemia minor.
  • Deletion of both copies of delta and both copies of beta subunits results in symptoms similar to beta-thalassemia intermedia.

How Common Are Thalassemia Conditions?

Not all people who carry a thalassemia-associated genetic mutation have symptoms.

For example, the most common thalassemia is alpha-thalassemia silent carrier (inactivation of 1 alpha subunit gene copy). It is not clinically significant due to a lack of symptoms [13].

Beta thalassemia minor is also a relatively common condition, especially in some parts of the world. It is common in the Mediterranean, Middle-East, Transcaucasus, Central Asia, Indian subcontinent, and Far East regions and in people of African descent [14, 15, 16, 17, 18].

Multiple studies, including one meta-analysis, concluded that some thalassemia mutations may offer protection from malaria, which could explain its prevalence in areas where malaria is common [14, 15, 16, 17, 18].

Recent trends in migration have changed these dynamics and thalassemia is now also prevalent in northern Europe, North and South America, the Caribbean, and Australia [5, 13].

Symptoms & Diagnosis

Symptoms

Thalassemia may develop in the first two years of life, but babies show signs and symptoms of thalassemia at birth.

People who have a less severe form of the disease (only one affected hemoglobin gene) may not have thalassemia symptoms.

People with thalassemias conditions generally have similar symptoms, with the severity of the symptoms depends on the number of defective or absent genes.

Therefore, symptoms shown here are commonly associated with thalassemia. See your doctor for an accurate evaluation and diagnosis.

The following have been associated with milder forms of thalassemia [5, 6, 1]:

  • Anemia
  • Delayed or stunted growth
  • Diarrhea
  • Feeding problems in infants
  • Irritability
  • Mild jaundice (yellowing of the skin and the whites of eyes)
  • Pale skin/pallor
  • Recurrent fever

Milder forms of thalassemia may be misdiagnosed or identified quite late in life. These complications may arise later [5, 6, 1]:

  • Enlarged stomach due to an enlarged liver or spleen
  • Bone deformities and fractures
  • Hemoglobin H patients develop gallstones and experience hemolysis (destruction of red blood cells) as a side effect of drugs and infections.
  • Iron overload can occur due to repeated blood transfusions or increased iron absorption [19].

When to See a Doctor

If your child has symptoms of thalassemia, schedule a doctor’s appointment to ensure they get adequate evaluation, diagnosis, and treatment.

Similarly, be sure to talk to your doctor if you experience any symptoms of the disease. Milder forms of thalassemia may arise later in life and getting proper medical care is important.

Laboratory Tests

If your doctor suspects your child has thalassemia, he or she will usually order blood tests to confirm a diagnosis. These blood tests reveal the size and appearance of the red blood cells and levels of specific hemoglobin.

Rarely, thalassemia is diagnosed later in life.

Small and pale red blood cells indicate low levels of hemoglobin, as hemoglobin is what makes the blood cells red and low levels of hemoglobin result in smaller cells. In mammals, red blood cells usually don’t contain a nucleus (the brain of the cell), except in babies. Thus, the presence of red blood cells with a nucleus in adults could indicate thalassemia (fetal hemoglobin) [6, 20].

Small, pale red blood cells would indicate thalassemia, in general [6, 5].

Hemoglobin H disease should also have a higher rate of red blood cell death (hemolytic anemia). Red blood cells with nuclei and decreased adult hemoglobin levels with increased fetal hemoglobin level would indicate beta-thalassemias [6, 5].

Rare forms of thalassemia may also be diagnosed during pregnancy.

In hemoglobin Bart syndrome, an ultrasound would reveal a thickened placenta and build-up of fluid around major organs in the fetus [6, 5].

Genetic Tests

Genetic tests can reveal which genes have a mutation or deletion and therefore, detect the thalassemia type (or types) [6, 5].

These genetic tests are considered helpful because they may provide more precise information than blood lab markers [6, 5].

Siblings of people with severe thalassemias can also get molecular genetic testing for known harmful SNPs in the family or blood testing if the harmful SNPs in the family are not known [6, 5].

Treatment of Thalassemia

Overview

People with mild forms of thalassemia usually don’t require treatment.

Based on the symptoms, patients with moderate to severe thalassemia may need [6, 5, 21]:

  • Red blood cell transfusions (occasional or chronic)
  • Chelation therapy (binding and removal of excess iron) for iron overload that can result from regular transfusions
  • Stem cell transplant
  • Removal of the spleen (splenectomy)
  • Surgery for gallstones and leg ulcers
  • Radiotherapy or hydroxyurea (a drug) to prevent the formation of red blood cells outside the marrow
  • Vitamin or mineral supplements if deficient

Blood Transfusions

If hemoglobin Bart syndrome is diagnosed early in the prenatal period, blood transfusions within the uterus (intrauterine transfusions) and stem cell transplants can improve the outlook and reduce mortality [22].

Blood transfusion is the standard therapy for severe forms of thalassemia (beta-thalassemia major, severe hemoglobin E/beta-thalassemia, hemoglobin H constant spring, and hemoglobin Bart syndrome) to maintain hemoglobin levels and reduce the production of defective red blood cells [1, 23].

Regular transfusion can prevent or eliminate the side effects of defective red blood cell production. However, it can lead to long-term iron overload (too much iron in the blood), which requires additional treatment [1, 23].

Transfusions are usually given every two to four weeks [21, 6].

Possible complications of iron overload from blood transfusions include stunted growth and failure or delay of sexual maturation in children as well as heart conditions, HIV, hepatitis, enlarged spleen, osteoporosis, and imbalanced hormones in adults [5].

New Therapies For Thalassemias

The following have been suggested as new therapies for more severe forms of thalassemia:

Bone marrow transplantation is an option for some people with thalassemia, particularly children with beta-thalassemia. If successful, it can eliminate the need for blood transfusions and iron chelation [5].

Umbilical cord blood transplantation has been proposed as a successful cure for beta-thalassemia, with lower risks as compared to bone marrow transplantation. However, it’s still experimental and a relatively complex procedure. More research is needed [24].

Gene therapy, or using stem cells modified to produce beta globins or by reactivating fetal hemoglobin, is undergoing research for treatment of alpha- and beta-thalassemias [5, 25, 26].

The effectiveness of these emerging therapies is still relatively unknown, but they have shown promise in clinical settings.

Pregnancy Management

Pregnant women carrying a child with hemoglobin Bart syndrome are at risk for complications such as high blood pressure and premature delivery or miscarriage [6].

Pregnant women with hemoglobin H disease may experience exacerbated anemia, high blood pressure, and miscarriage and other complications [6].

Pregnant women with beta-thalassemia may experience complications such as heart failure, infections, and possibly the body rejecting a blood transfusion [27, 28].

These conditions all require careful management, monitoring, and treatment.

Other

Limited evidence suggests that people with alpha-thalassemias should not be prescribed oxidant drugs, such as sulphonamides and some antimalarial medication because of the risk of red blood cell destruction [6].

Coping With Thalassemia

Precautions

You may try the complementary approaches listed below if you and your doctor determine that they could be appropriate. Read through and discuss the strategies listed here with your doctor. Remember that none of them should ever be done in place of what your doctor recommends or prescribes.

Psychological Support

Getting support can help you cope with your or your child’s thalassemia. Don’t hesitate to seek support. Talk to your healthcare provider about getting additional help. Seeing a counselor, psychotherapist, or joining a support group are some options you can consider.

Genetic Counseling

Genetic counseling can help people understand their genetic tendencies and better cope with inherited diseases. It may also be helpful in relatives of people who have thalassemia, especially for types of thalassemias that may arise later and negatively affect the quality of life.

When focused on siblings, research suggests that genetic counseling can help people understand that a sibling of a person with beta-thalassemia has [5]:

  • A 25% chance of being affected
  • A 50% chance of being a carrier with no symptoms
  • A 25% chance of being unaffected and not a carrier

It may also aid thalassemia prevention when done as part of preconception counseling in couples. This may be particularly important if one of the parents is a carrier and in parts of the world where thalassemia is relatively common [29].

For example, up to 40% of Tribal children in Bangladesh carry Hb-E. The majority of children with severe thalassemias are born in countries with limited resources where the top priority tends to be to reduce high infant and child mortality rates from infection and malnutrition. Genetic counseling has been suggested as a helpful but underused prevention strategy [29].

Diet & Nutritional Assessment

Research suggests that thalassemia patients should closely monitor their diet to increase their quality of life.

Eating a nutritious, healthy diet can help people with thalassemia feel better.

Thalassemia conditions can cause stunted growth during childhood. Thalassemia patients commonly have nutritional deficiencies [30, 31].

Therapies for thalassemia often results in iron overload, which can cause many issues. Regular nutrition check-ups may help prevent complications [30, 31].

The nutritional requirements described below are by no means complete. Only an expert nutritionist can give a personalized insight into dietary requirements based on deficiencies. Nutritional counseling is essential for [30]:

  • Pregnant patients
  • Diabetics
  • Vegetarians or vegans
  • Lactose intolerant patients
  • Patients with food allergies

Common Vitamin and Mineral Deficiencies

Research suggests that the following vitamin deficiencies are common in thalassemia patients [30, 32, 33, 21, 34]:

Avoiding Iron

Beta-thalassemia patients should avoid alcohol consumption and iron-containing preparations [5].

Therefore, people with thalassemia should not take vitamins or other supplements that contain iron unless recommended by a doctor.

Even transfusion-independent patients can develop iron overload. To reduce dietary iron, avoid red and organ meats, and fortified breakfast cereals that are high in iron [30, 23].

Natural Substances that May Reduce Iron Buildup

Some natural substances such as tea and curcumin (turmeric) have been suggested to reduce iron absorption. However, their impact on iron overload in patients with thalassemia is unknown.

Tea (275 mg tannins/240 mL water) reduced iron absorption by 41-95% in 5 thalassemia patients, but large-scale studies are lacking. Since patients with thalassemia absorb a large percentage of iron, inhibitors of iron absorption are being further researched for iron overload in thalassemia [35].

A daily dose of 500mg of curcumin (an active component of turmeric) reduced blood iron levels and oxidative stress in 21 hemoglobin E/beta-thalassemia patients [36].

A similar study showed curcumin (1,000 mg/day for 12 weeks) decreased blood iron levels by 18% in the curcumin group (DB-RCT of 68 transfusion-dependent beta-thalassemia patients). More research is needed to determine the effectiveness and safety of curcumin in thalassemia patients [37].

Thalassemia Genetics and SNPs

Limitations

Because thalassemias conditions involve over 300 different known mutations, with a wide variety of complications, it is difficult to develop a complete picture of the disease [1].

Therefore, the list below is not comprehensive: it does not include all possible genetic variations that can influence thalassemia risk or severity.

A Note About SNPs

A SNP (pronounced “snips”) or single nucleotide polymorphism is a single change (polymorphism) to one of the DNA building blocks (nucleotide).

SNPs are normal and occur every 300 nucleotides or so, meaning there are approximately 10 million SNPs in everyone’s genomes. Sequencing your genes can locate your SNPs [38].

It’s important to note that just because certain SNP genotypes are associated with a disease, it doesn’t necessarily mean that everyone with that genotype will actually develop the disease. Many different factors, particularly other stronger genetic factors outlined in the previous parts of this post, can influence thalassemia.

SNPs Associated with Reduced Thalassemia Symptoms

Thalassemias are a very complicated set of genetic diseases, as different thalassemias can occur simultaneously. Some genetic combinations have been associated with a decreased severity of symptoms. For instance, reduced production of both alpha and beta subunits can actually decrease the imbalance between these subunits [39, 5].

The C variant of rs11886868 in the BCL11A gene may reduce the severity of beta-thalassemia due to increased production of fetal hemoglobin [40].

Similarly, beta-thalassemia patients with the rs7482144 SNP respond better to a drug that raises hemoglobin levels (hydroxyurea). This SNP also increases fetal hemoglobin levels and reduces the need for frequent blood transfusions [41, 42, 43].

Alpha-Subunit Genes (HBA1, HBA2)

Some SNPs related to alpha-thalassemia and their potential associations:

  • rs41417548 (Hb Sallanches): risk of hemoglobin H disease [44, 45]
  • rs41323248 (Hb Dartmouth): risk of hemoglobin H disease [46]
  • rs34021271 (Hb Pak Num Po): transfusion-dependent hemoglobin H disease [47]
  • rs41464951 (Hb Constant Spring): hemoglobin H disease or carrier [48]
  • rs41412046 (Hb Pakse): hemoglobin H disease or carrier [49]
  • rs41341344 (Hb Agrinio) [50]
  • rs35992350 (Hb Heraklion) [51]
  • rs35672478 (Hb Aghia Sophia) [52]

Beta-Subunit Genes (HBB)

SNPs that have been associated with an increased risk of beta-thalassemia:

Delta-subunit Genes (HBD)

Following SNPs have been described as risk variants for delta-thalassemia:

Research suggests that changes in hemoglobin genes may increase the risk of developing other genetic conditions like osteoporosis. Personalized genetic counseling has been suggested to increase the quality of life of thalassemia patients [66].

About the Author

Ana Aleksic

Ana Aleksic

MSc (Pharmacy)
Ana received her MS in Pharmacy from the University of Belgrade.
Ana has many years of experience in clinical research and health advising. She loves communicating science and empowering people to achieve their optimal health. Ana spent years working with patients who suffer from various mental health issues and chronic health problems. She is a strong advocate of integrating scientific knowledge and holistic medicine.

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