All about Thalassemia (A Blood Borne Disease)

Background

Thalassemia is an autosomal recessive blood disorder. In thalassemia, the genetic defect results in reduced rate of synthesis of one of the globin chains that make up hemoglobin. (Hemoglobin is made up of 4 polypeptide subunit: 2 alpha globin chain + 2 beta globin chain). The reduced synthesis of one of the globin chains can cause the formation of abnormal hemoglobin molecules, and hence causing anemia.

There is two kind of thalassemia which is alpha thalassemia, whereby the alpha globin chain is affected, and beta thalassemia, whereby the beta globin chain is affect.

Thalassemia (alpha and beta) is also classified as two form: thalassemia major and thalassemia minor

Thalassemia major occurs when defective genes are inherited from both parents while 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 have very mild or do not have any symptoms at all.

 Four genes, two genes (HBA1 and HBA2) from each parents, are required to form the alpha globin chain. The severity to alpha thalassemia depends on how many genes are missing or mutated. When only one of the genes are affected, it has a minimal effect on the carrier.
There would be no clinical symptoms as 3 alpha globin genes are enough to allow normal hemoglobin production. Those who has only one alpha gene affected are called the “silent carriers”.

An Alpha thalassemia trait occurs when two of the 4 genes are affected. Although 2 genes are enough to allow nearly normal erythropoiesis, affected individuals may still have mild microcytic hypochromic anemia (red blood cells are paler and smaller than normal). Individuals who are develop this anemia may sometime experience lack of energy, shortness of breath, dyspepsia, headaches, a capricious or scanty appetite and amenorrhea.

Severe alpha thalassemia occurs when more than 2 gene are affected. When 3 genes are affected, one would develop a condition call Hemoglobin H disease where by the hemoglobin (Hemoglobin Barts and Hemoglobin H) present in the blood are unstable. These unstable hemoglobin has a high affinity for oxygen than in normal hemoglobin and hence causing poor oxygen delivery to the tissues. Severe alpha thalassemia occurs when 4 genes are affected, this results in hydrops fetalis whereby they cannot live once outside the uterus and are not able to survive gestation.

Alpha thalassemia occur most commonly in individuals from the southeast Asia (SEA), the Middle East, China, and in those of African descent.

TreatmentAffected individuals with mild forms of alpha thalassemia (with only one or two genes affected) may not require specific treatment however there may be a need for management of low hemoglobin levels via supplements like iron or folic acid. Patients with more severe anemia may require lifelong regular blood transfusion therapy. Children with alpha thalassemia may require bone marrow transplant in order to treat the disease.

HBB gene is important for the making of beta-globin, a subunit of hemoglobin. Studies have shown that there is more than 250 mutation in HBB gene that cause beta thalassemia. Most mutation involve a change in single DNA nucleotide within or near the HBB gene, while other mutation involves insert or deletion of a small number of nucleotide in HBB gene.  

People with HBB mutations can be diagnosed with thalassemia major and thalassemia intermediate.

In Beta Thalassemia minor, only one out of the two beta globin genes is mutated. This is insufficient to cause a problem in the normal functioning of hemoglobin. Individual with Beta Thalassemia minor will only carry the genetic trait and will not experience any health issues.

Beta-Thalassemia Major (also known as Cooley’s anemia) is a autosomal recessive disorder, which require the inheritance of two copies of mutated beta globin gene (one from each parent) to develop the symptoms.  Hence, both parents have to be beta-thalassemia minor.
The lack of beta globin will result in a life-threatening anemia. It will reduce the production of hemoglobin which is important for the body by transporting oxygen in red blood cells around the body.  

Beta Thalassemia Major is a blood disorder, also known as the Cooley’s anemia. There will be a shortage of red blood cells, which will lead to many serious complications.

Signs and symptoms will show within the first 2 years of life. Children will not gain weight and may develop jaundice. They may have enlarged spleen, heart and liver. Adolescents may experience delayed puberty.

Treatment
There is currently no cure for people affected by Beta-Thalassemia Major. Individuals with beta-thalassemia major will require frequent blood transfusion and extensive medical care to replenish red blood cell supply. They have to undergo therapy for removal of excess iron in the body due to the transfusion. The excess amount of iron-containing hemoglobin from the blood transfusions build up in the body, and will cause damage to the liver and heart, thus, leading to other liver, heart and hormone problems. 

Article that link Beta-Thalassemia to fertility

Title: Living with Thalassemia

<http://cooleysanemia.org/updates/Pregnancy2.pdf> 

For many years, people assumed that the iron overload is seen in beta thalassemia patients is due to the frequent blood transfusion therapy (can give rise excess amount of iron-containing hemoglobin in the body) alone. However, recent studies have shown that patients with beta-thalassemia intermedia who has not undergo blood transfusion therapy have “higher-than-average” iron stores. For example the rate of iron uptake in the gut were 3 to 4 times higher than normal.

Besides the health problem that iron overload can cause, it can also affect the development of both male and female sex organ which in turn can affect the reproductive capabilities of a person with thalassemia. The article which we have choose to research on is based on the experiences and stories of individuals that has undergo careful interview by a panel of experts but has not been published in a medical journal.

Individuals with thalassemia may experience delayed puberty, due to the deficiency of hormones (testosterone and estrogen) necessary for sexual maturation cause by iron overload. Although many eventually would enter puberty, some do not reach sexual maturity and thus has a complication called “hypogonadism”. For females, those who never begin menses are said to have primary amenorrhea, while those who transiently have menses are said to have secondary amenorrhea. Delayed puberty, hypogonadism and amenorrhea are signs of hormone deficiency and hence may likely cause fertility problem.  For example, most affected males are not able to produce adequate amount of sperms and affected females do not ovulate.

Scientific report: Beta-Thalassemia Major and Female Fertility

Scientific report

The below research article will discuss the role of thalassemia on fertility of affected individuals.  The article will also discusses how the role of increased iron and iron-induced OS can affect the fertility of females with Beta-Thalassemia Major.

Title: Beta-Thalassemia Major and Female Fertility: The Role of Iron and Iron-Induced Oxidative Stress.

<http://www.ncbi.nlm.nih.gov/pubmed/24396593>

Introduction:
Iron overload is a result of multiple blood transfusions and inappropriate increase of iron absorption. The amount of catabolic iron exceeds the iron-carrying capacity of transferrin, thereby causes the emergence of non-transferrin-bound iron (NTBI). NTBI catalyzes the formation of free radicals, thus causes oxidative stress and damage to organelles in cells.
Hemosiderosis is a type of iron overload disorder which causes endocrine complications. Majority of the females with Beta-thalassemia Major (BTM) is infertile because of hypogonadotropic hypogonadism. Iron deposition and iron-induced oxidative stress occurs in endocrine organs, such as hypothalamus, pituitary gland, and the female reproductive system. They also affect the liver and pancreas. BTM patients have intact gonads and fertility is usually retrievable.

Treatments:
Antioxidant supplements such as Vitamin C and Vitamin E are used in BTM children. They help to enhance liver functions. Glutamin, alpha-lipoic acid, acetyl-L-carmitine, and N-acetylcysteine are also studied as antioxidant supplements for BTM. They are also variably effective in oxidative stress induced male infertility by improving semen parameters and pregnancy rates.
Chelation treatments are also used as antioxidants in BTM. They inhibit the catalytic activity in formation of free radicals and oxidative stress in tissue damage. There is a lower oxidative stress level in patients who had undergone chelation treatments.

Conclusion:
Oxidative Stress plays an important role in the pathophysiology of infertility in females with BTM. It is a result of tissue injury due to the overproduction of free radicals by secondary iron overload, alteration in serum trace elements and antioxidant enzymes level.
Antioxidants can improve the pathophysiology of thalassemia. Treatment would reduce oxidative stress in reproductive tract of BTM women.
Many researches are in progress to find out the mechanisms that cause infertility, effective ways to counteract oxidative stress, and evaluate the antioxidant supplementation in BTM females.