Thalassemia is a genetic blood disorder that causes the body to produce fewer red blood cells and hemoglobin. A bone marrow transplant is the only thalassemia major treatment.

Thalassemia (Major and Minor)

Thalassemia is a genetic blood disorder that causes the body to produce fewer red blood cells and hemoglobin. A bone marrow transplant is the only thalassemia major treatment. In Urdu, Thalassemia is known as "تھیلیسیمیا" (Thalassemia meaning in Urdu).

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Iqra Mazhar

Overview

The Thalassemia International Federation (TIF) defines it as an inherited blood disorder characterized by decreased haemoglobin production. Also called &#39;Cooley&#39;s anaemia&#39; after Dr. Thomas Cooley, thalassemia is the most common genetic blood disorder, affecting 4.4 out of 10,000 live births.<a href="#accordion">[1]</a>&nbsp;In Pakistan, approximately 5,000-9,000 children with the blood disorder are born every year.<a href="#accordion">[2]</a>&nbsp;Thus, placing it among the highest thalassemia burden countries in the world.

In the early 1920s, Dr. Thomas Cooley and Dr. Pearl Lee noticed a strange form of anaemia among Italian and Greek children. Along with a low red blood cell count, the children also exhibited poor growth and had enlarged abdominal organs. Moreover, the mysterious disease seemed to predominantly affect people living near the Mediterranean Sea. Hence, the name thalassemia was coined, derived from the Greek word &#39;Thalassa&#39; meaning &#39;sea&#39;. However, today, the disease is not only common in the Mediterranean region but also in South-East Asia, the Middle East, Central Asia, Africa, and the Indian subcontinent.&nbsp; 
&nbsp;

A haemoglobin molecule is made up of two alpha-globin and two beta-globin protein chains. Production of the alpha chain is dependent on four alpha genes - two are inherited from each parent; the beta-globin chain is controlled by two beta genes - one is inherited from each parent. A genetic mutation or deletion of alpha or beta genes can result in thalassemia. Therefore, depending on these genetic changes, the blood disorder is divided into two main types: alpha and beta. Moreover, it is further divided into subtypes depending on the severity of the disorder. 
&nbsp;

<h5>Alpha Thalassemia&nbsp;</h5>

Mutation or deletion of the alpha genes results in the reduced production of the alpha globin chains. As a result, there&#39;s an accumulation of beta-globin chains within the red blood cells. The particular form of thalassemia is common in malaria-endemic regions around the world. It is believed that the alpha-globin gene deletions may provide protection against the parasite.&nbsp; 
&nbsp;

<ul>
	<li>Silent Carrier: A silent carrier only possesses one mutated alpha gene and has no signs or symptoms of thalassemia. However, the carrier can still pass the mutated gene to their children. 
	&nbsp;</li>
	<li>Alpha Thalassemia Minor: If a person inherits two mutated alpha genes, they will have mild <a href="http://www.merisehat.pk/disease/anemia">anemia</a>, known as thalassemia minor. Since their anemia is mild, they don&#39;t generally require any medical treatment. 
	&nbsp;</li>
	<li>Haemoglobin H (HbH) Disease: These people have inherited three mutated genes of alpha genes. Thus, resulting in insufficient or a lack of alpha globin chain. Since the beta-globin chains cannot pair up with alpha chains, they end up forming new hemoglobin, called HbH. Although HbH has a good oxygen-carrying capacity, it results in hemolysis. As a result, patients can suffer from moderate to severe anemia, and require lifelong blood transfusions. 
	&nbsp;&nbsp;</li>
	<li>Alpha Thalassemia Major:&nbsp;Also called hydrops fetalis, this severe form of thalassemia is incompatible with life. Four mutated genes result in an inability of the fetus to produce normal hemoglobin. As a result, babies are either born stillborn or die shortly after birth. 
	A meta-analysis conducted in Southeast Asia found a 22.6% prevalence of alpha thalassemia<a href="#accordion">[3]</a>.&nbsp;The highest prevalence was seen in Vietnam (51.5%) followed by Cambodia (39.5%), Laos (26.8%), Thailand (20.1%), and Malaysia (17.3%).<a href="#accordion">[3]</a></li>
</ul>

&nbsp;

<h5>Beta Thalassemia&nbsp;</h5>

Beta thalassemia results from a mutation or deletion of the beta-globin genes. It is further divided into: 
&nbsp;

<ul>
	<li>Beta Thalassemia Minor:&nbsp;Also known as thalassemia carriers, these people have only inherited one mutated beta-globin gene and suffer mild anemia. More than 9.8 million people in Pakistan are carriers.<a href="#accordion">[4]</a> 
	&nbsp;</li>
	<li>Thalassemia Intermedia:&nbsp;The clinical severity of the condition lies between thalassemia minor and major. Patients generally have a moderate form of anemia and require occasional blood transfusions. It is caused by the presence of one mutated gene or two defective or missing beta-globin genes.&nbsp; 
	&nbsp;</li>
	<li>Beta Thalassemia Major:&nbsp;This is characterized by moderate or severe <a href="http://www.merisehat.pk/disease/anemia">anemia&nbsp;</a>due to the person inheriting two mutated beta-globin genes. Regular blood transfusions are required to reduce <a href="http://www.merisehat.pk/disease/anemia">anemia</a>&nbsp;and prevent complications. 
	&nbsp;</li>
</ul>

Approximately, 1.5% of the world&#39;s population suffers from beta thalassemia.<a href="#accordion">[5]</a>In Pakistan, 5-7% of the population is affected by this blood disorder.<a href="#accordion">[2]</a> 
&nbsp;

Signs And Symptoms

Along with mild or severe anemia, people can also experience other symptoms. These include:

<ul>
	<li>Irritability&nbsp;</li>
	<li>Pale or yellow skin (<a href="https://www.merisehat.pk/disease/jaundice-65" target="_blank">jaundice</a>)</li>
	<li>Fatigue and excessive tiredness</li>
	<li>Feeling cold</li>
	<li>Delayed growth and development in children</li>
	<li>Poor appetite</li>
	<li>Dark urine</li>
	<li>Weak bones</li>
	<li>Abdominal swelling</li>
	<li>Increase in infections 
	&nbsp;</li>
</ul>

Causes

Haemoglobin is a protein present in red blood cells that helps carry oxygen. Adult hemoglobin (HbA) is composed of two alpha and two beta chains. Gene mutations in any one of these chain proteins result in an abnormal form of hemoglobin. As a result, the oxygen-carrying capacity of the red blood cells is affected. Moreover, there&#39;s increased destruction of the red blood cells, which results in <a href="http://www.merisehat.pk/disease/anemia">anemia</a>.&nbsp;

Alpha and beta thalassemia are autosomal recessive conditions. Both parents must be carriers to pass the defective gene to their child. If both parents are carriers, the child has a 25% risk of developing thalassemia. However, if a person only receives one mutated gene from a parent and one normal gene, then they will have thalassemia minor (also called thalassemia carrier or thalassemia trait). People with thalassemia trait do not have the disease but can pass the genes to their children.&nbsp;

In alpha-thalassemia, the severity of the disease is dependent on how many copies of the abnormal gene you inherit, whereas, in beta-thalassemia, the part of the hemoglobin molecule that is affected decides the severity. 
&nbsp;

<h4>"Thalassemia might lower your hemoglobin but not your oxygen saturation. Check out our <a href="https://www.merisehat.pk/page/sehat-scan/" target="_blank">sehat scan</a> and get your oxygen saturation level today!"</h4>

The American College of Obstetricians and Gynaecologists recommends screening of all pregnant patients for thalassemia, especially those belonging to high-risk ethnicities, such as Mediterranean, Middle Eastern, African, West Indian, and Southeast Asian.<a href="#accordion">[6]</a>A complete blood cell count (CBC) can be followed by hemoglobin electrophoresis in case of low mean red cell volume.&nbsp; 
&nbsp;

<h5>Prenatal Screening</h5>

Pregnant women, who want to learn whether their child will have the disorder, can undergo the following tests:

<ul>
	<li>Chorionic Villus Sampling (CVS):&nbsp;It is typically performed around the 11th week of pregnancy and involves removing a small piece of the placenta. DNA analysis is then conducted on the sample.</li>
	<li>Amniocentesis:&nbsp;Conducted during the 16th week of pregnancy, the test involves sampling and analysis of amniotic fluid surrounding the fetus.&nbsp;</li>
</ul>

If a fetal abnormality or hemoglobinopathy is detected, the parents should be referred for genetic counseling.&nbsp; 
&nbsp;

<h5>Premarital Screening</h5>

In Pakistan, consanguineous marriages are highly prevalent. This has led to an increase in the incidence and burden of genetic disorders such as thalassemia. Therefore, the Punjab Thalassemia Prevention Programme (PTPP) includes a premarital screening option to identify at-risk couples. In the provinces of Sindh and Balochistan, laws for premarital screening of thalassemia have already been implemented.<a href="#accordion">[7][8]</a>&nbsp;Through the identification of asymptomatic carriers, the screening program aims to reduce the rate of high-risk marriages and the birth of affected children.<a href="#accordion">[9]</a> 
 
Several other countries have also set premarital screening laws for this inherited blood disorder. In Cyprus, a combination of premarital and prenatal screening helped reduce the number of children born with the disease from 1 in every 158 births to almost zero.<a href="#accordion">[10]</a>&nbsp;Similarly, in Saudi Arabia, 6 years after the implementation of a premarital screening program, there was a more than 70% reduction in the prevalence of beta thalassemia.<a href="#accordion">[11]</a>&nbsp;However, such screening programs can only be successful if there is mass education of the population regarding the blood disorder.&nbsp; 
&nbsp;

<h5>Carrier Screening</h5>

More than 5% of Pakistan&#39;s population is a beta thalassemia carrier.<a href="#accordion">[2]</a>&nbsp;Identification of these carriers can help reduce the disease burden in the country. As a result, the PTPP provides free carrier screening for entire families. Extended family screening is also available for families with a thalassemia major child.&nbsp; 
 
All screening tests involve a CBC and hemoglobin electrophoresis. 
&nbsp;

Diagnosis

Most children with thalassemia are born healthy but develop symptoms within the first two years of their life. Before conducting any tests, the doctor will take a detailed history and perform a physical examination. During a physical exam, patients are assessed for signs of thalassemia, such as facial bone deformities, an enlarged spleen, and abdominal swelling.&nbsp; 
 
The blood tests used for diagnosing thalassemia include: 
&nbsp;

<ul>
	<li>Complete Blood Count (CBC):&nbsp;The test provides values for hemoglobin levels and red blood cell count and size. In thalassemia, people will have low red blood cells&nbsp;and reduced hemoglobin levels, and the red blood cells may be smaller than normal. 
	&nbsp;</li>
	<li>Iron Profile:&nbsp;An iron profile test helps rule out iron deficiency as the cause of anemia.&nbsp; 
	&nbsp;</li>
	<li>Reticulocyte Count:&nbsp;Reticulocytes are immature red blood cells produced by the bone marrow. These are released into the bloodstream and take around 2 days to mature into adult red blood cells. If one&#39;s red blood cell count is too low, the bone marrow produces more reticulocytes. A reticulocyte count demonstrates whether the bone marrow produces enough red blood cells.&nbsp; 
	&nbsp;</li>
	<li>Haemoglobin Electrophoresis:&nbsp;This blood test analyses the red blood cells for different types of hemoglobin. Adult red blood cells predominantly contain hemoglobin A (95%), and small amounts of fetal hemoglobin (HbF) and hemoglobin A2.<a href="#accordion">[12]</a>&nbsp;In beta thalassemia minor, higher than normal levels of HbF and hemoglobin A2&nbsp;are seen. On the other hand, beta thalassemia major is characterized by low HbA levels and increased HbF levels. 
	&nbsp;</li>
	<li>Genetic Testing:&nbsp;A DNA analysis can help detect mutated genes associated with alpha thalassemia.&nbsp;&nbsp; 
	&nbsp;</li>
</ul>

Treatment

People with a mild form of thalassemia don&#39;t generally need any medical treatment. However, they may be advised lifestyle changes that include taking folic acid supplements, eating a low-iron and low-fat diet, vitamin D and calcium supplements, and practicing good hygiene to prevent infections.&nbsp;In the case of moderate to severe <a href="http://www.merisehat.pk/disease/anemia">anemia</a>, people might require various treatments. These include: 
&nbsp;

<h5>Blood Transfusion&nbsp;</h5>

This involves transferring donated blood into the patient&#39;s body. Severe forms of thalassemia usually require transfusions every few weeks. The frequency of these transfusions depends on the severity of the condition. People with beta-thalassemia major typically receive a transfusion every 2-4 weeks. A build-up of iron is a common side effect of frequent blood transfusions. Moreover, there is also an increased risk of transfusion-transmitted infections.&nbsp; 
 
In Pakistan, there is a high incidence of hepatitis B and C infections in chronic transfusion recipients such as thalassemia patients.<a href="#accordion">[14]</a>&nbsp;This is mostly due to improper screening and evaluation of donated blood products. However, currently, measures are being taken to curb these issues.&nbsp;&nbsp; 
&nbsp;

<h5>Iron Chelation&nbsp;</h5>

Elevated iron levels in the blood are common in thalassemia patients. This results as a side effect of multiple blood transfusions and from increased hemolytic anemia and intestinal iron absorption in patients. The increased iron in the bloodstream can damage organs. Therefore, thalassemia patients often require medications such as deferoxamine, deferiprone, and deferasirox. This help removes the excess iron from the body.&nbsp; 
&nbsp;

<h5>Surgery&nbsp;</h5>

In thalassemia patients with an enlarged spleen, a splenectomy (surgical removal of the spleen) might be needed.&nbsp; 
&nbsp;

<h5>Bone Marrow Transplant&nbsp;</h5>

Also called stem cell transplant, it is the only cure for thalassemia. The procedure involves transplanting healthy stem cells from a donor to the recipient. These stem cells produce healthy blood cells in the donor&#39;s body, Thus, replacing the damaged and defected red blood cells affected by thalassemia. However, the procedure carries multiple risks including a risk of graft versus host disease. Therefore, a bone marrow transplant is only considered for people with severe forms of thalassemia in whom the benefits outweigh the risks.&nbsp; 
&nbsp;

<h5>Hydroxyurea&nbsp;</h5>

Although hydroxyurea is FDA-approved for use in sickle-cell anemia, it has been shown to significantly improve clinical abnormalities in patients with beta-thalassemia intermedia.<a href="#accordion">[13]</a>&nbsp;The cytotoxic drug works by increasing levels of HbF, the overall hemoglobin, and the mean red blood cell volume. 
&nbsp;

People with moderate to severe thalassemia can suffer from various complications. These include:

<ul>
	<li>Iron Overload:&nbsp;Excess iron in the body can get deposited in the heart, liver, muscles, and endocrine glands. As a result, people can develop <a href="https://www.merisehat.pk/disease/diabetes-type-1-and-2" target="_blank">diabetes</a>, heart dysfunction, <a href="https://www.merisehat.pk/disease/hypothyroidism" target="_blank">hypothyroidism</a>, <a href="https://www.merisehat.pk/disease/infertility-in-men" target="_blank">infertility</a>, and liver fibrosis.&nbsp; 
	&nbsp;</li>
	<li>Splenomegaly:&nbsp;An excessive breakdown of the red blood cells results in an enlargement of the spleen. 
	&nbsp;</li>
	<li>Bone Deformities:&nbsp;The increased hemolysis activates the bone marrow, resulting in increased bone growth, especially in the facial bones. The deformed bones of the skull and face can give the person a strange appearance. 
	&nbsp;</li>
	<li>Osteoporosis:&nbsp;The bones become weak and brittle with an increased risk of fractures. 
	&nbsp;</li>
	<li>Gallstones:&nbsp;There is an increased frequency of gallstones in people with thalassemia. 
	&nbsp;</li>
	<li>Transfusion Reaction:&nbsp;Blood transfusions can also cause an allergic reaction in the recipient. The recipient&rsquo;s immune system begins to attack the red blood cells, causing their destruction. The patient may experience fever, chills, nausea, diarrhoea, and low blood pressure. 
	&nbsp;</li>
	<li>Heart Problems:&nbsp;Arrhythmias and congestive heart failure can develop in thalassemia patients. 
	&nbsp;</li>
	<li>Delayed Puberty:&nbsp;People are generally shorter than usual due to slow growth. Moreover, gonadal dysfunctioning from iron overload can delay puberty in patients. 
	&nbsp;</li>
</ul>

The following factors increase a person&#39;s risk of thalassemia:

<ul>
	<li>Ethnicity:&nbsp;Certain ethnicities such as the Mediterranean, Southeast Asian, and African Americans have a greater chance of inheriting the gene mutation. 
	&nbsp;</li>
	<li>Family History:&nbsp;Since thalassemia is a genetic disorder, a family history of thalassemia means there&rsquo;s a higher risk of the mutated gene being passed on to the child. 
	&nbsp;</li>
</ul>

Since thalassemia is a genetic disorder, there is no way to prevent it. However, as an adult, you can find out whether you carry the thalassemia trait and your chance of passing the genes on to your child.&nbsp;

Along with effective screening programs, there is a need for community-level health education programs. Moreover, couples with the thalassemia trait should be offered genetic counseling to educate them on their risk of having a child affected by the disorder and the economic and mental cost of living with thalassemia. 
&nbsp;

Key Points

<ul>
	<li>Thalassemia is an inherited blood disorder that results from a mutation of the gene responsible for alpha- or beta-globin chains of the haemoglobin molecule. As a result, the affected person has low haemoglobin levels and fewer red blood cells.&nbsp;</li>
	<li>The autosomal recessive condition occurs when a person inherits one or both copies of the mutated gene. If both parents are carriers, a person&#39;s risk of having thalassemia is 25%.&nbsp;</li>
	<li>Depending on the type of haemoglobin chain that is mutated, thalassemia can be divided into two main types: alpha and beta-thalassemia. These two are then further subdivided into minor or major depending on the severity of the hemoglobinopathy.&nbsp;</li>
	<li>Other than anaemia (ranging from mild to severe), people can also develop <a href="https://www.merisehat.pk/disease/jaundice-65" target="_blank">jaundice</a>, fatigue, weakness, abdominal swelling, brittle bones, slow growth, and enlarged spleen.</li>
	<li>Treatment options for thalassemia depend on the severity of the disease. It includes lifestyle changes, blood transfusions, chelation therapy, and hydroxyurea. A stem cell transplant is the only cure for the blood disorder. However, it carries with it several risks.</li>
	<li>Although thalassemia cannot be prevented, effective screening programs can help reduce the disease burden and identify at-risk members in the community. However, these screening programs can only be effective with the help of healthcare providers and religious leaders spreading health awareness among the masses.</li>
</ul>

[1] Kadhim, K. A., Baldawi, K. H. & Lami, F. H., 2017. Prevalence, Incidence, Trend, and Complications of Thalassemia in Iraq. Hemoglobin, 41(3), pp. 164-168.

[2] Ahmed, S., Saleem, M., Modell, B. & Petrou, M., 2002. Screening extended families for genetic hemoglobin disorders in Pakistan. New England Journal of Medicine, 347(15), pp. 1162-8.

[3] Wah Goh, L. P., Chong, E. T. J. & Lee, P.-C., 2020. Prevalence of Alpha(α)-Thalassemia in Southeast Asia (2010-2020): A Meta-Analysis Involving 83,674 Subjects. International journal of environmental research and public health, 17(20).

[4] Ghafoor, M., Sabar, M. F. & Sabir, F., 2021. Prevention programmes and prenatal diagnosis for beta thalassemia in Pakistan: A narrative review. Journal of the Pakistan Medical Association, 71(1).

[5] Colah, R., Gorakshakar, A. & Nadkarni, A., 2010. Global burden, distribution and prevention of β-thalassemias and hemoglobin E disorders. Expert Review of Hematology, 3(1), pp. 103-117.

[6] American College of Obstetricians and Gynecologists, 2017. Committee Opinion No. 691: Carrier Screening for Genetic Conditions. Obstetrics and gynecology, 129(3), pp. e41-e55.

[7] PROVINCIAL ASSEMBLY OF SINDH , 2014. THE SINDH PREVENTION AND CONTROL OF THALASSEMIA ACT, 2013. , Karachi: s.n.

[8] Balochistan Provincial Assembly Secretariat, 2015. THE BALOCHISTAN PREVENTION AND CONTROL OF THALASSEMIA ACT 2015 (ACT NO.XIV OF 2015), Quetta: s.n.

[9] Punjab Thalassemia Prevention Programme, 2015. Carrier Screening. [Online]

[10] Leung, T. N., Lau, T. K. & Chung, T. K., 2005. Thalassaemia screening in pregnancy. Current opinion in obstetrics & gynecology, 17(2), pp. 129-134.

[11] Memish, Z. A. & Saeedi, M. Y., 2011. Six-year outcome of the national premarital screening and genetic counseling program for sickle cell disease and β-thalassemia in Saudi Arabia. Annals of Saudi medicine, 31(3), pp. 229-235.

[12] Keohane, E. M., Smith, L. & Walenga, J. M., 2015. Rodak's Hematology: Clinical Principles and Applications. 5th Edition ed. s.l.:Elsevier Health Sciences.

[13] Keikhaei, B., Yousefi, H. & Bahadoram, M., 2015. Clinical and Haematological Effects of Hydroxyurea in β-Thalassemia Intermedia Patients. Journal of Clinical and Diagnostic Research, 9(10).

[14] Zaheer, H. A., Waheed, U., Abella, Y. E. & Konings, F., 2020. Thalassemia in Pakistan: A forward-looking solution to a serious health issue. Global Journal of Transfusion Medicine, 5(1), pp. 108-110.