Thalassemia

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Thalassaemia
)

Thalassemia
Other namesThalassaemia, Mediterranean anemia
folic acid[4]
Frequency280 million (2015)[5]
Deaths16,800 (2015)[6]

Thalassemias are inherited

pale skin.[1] Other symptoms of thalassemia include bone problems, an enlarged spleen, yellowish skin, pulmonary hypertension, and dark urine.[1] Slow growth may occur in children.[1] Symptoms and presentations of thalassemia can change over time. Thalassemia is also known as cooley's anemia or Mediterranean anemia.[citation needed
]

Thalassemias are

beta globin are missing.[2] Diagnosis is typically by blood tests including a complete blood count, special hemoglobin tests, and genetic tests.[3] Diagnosis may occur before birth through prenatal testing.[8]

Treatment depends on the type and severity.

heart or liver disease, infections, and osteoporosis.[1] If the spleen becomes overly enlarged, surgical removal may be required.[1] Thalassemia patients who do not respond well to blood transfusions can take hydroxyurea or thalidomide, and sometimes a combination of both.[10] Hydroxyurea is the only FDA approved drug for thalassemia. Patients who took 10 mg/kg of hydroxyurea every day for a year had significantly higher hemoglobin levels, and it was a well-tolerated treatment for patients who did not respond well to blood transfusions.[11] Other known hemoglobin-inducers include thalidomide, but it has not been tested in a clinical setting. The combination of thalidomide and hydroxyurea resulted in hemoglobin levels increasing significantly in transfusion-dependent and non-transfusion dependent patients [12]

As of 2015, thalassemia occurs in about 280 million people, with about 439,000 having severe disease.

sickle-cell trait, have some protection against malaria, explaining why sickle-cell trait and thalassemia are more common in regions of the world where the risk of malaria is higher.[15]
An estimated 1/3 of people with thalassemia have "non-transfusion dependent thalassemia" and do not depend on regularly continuing blood transfusions to survive.

Signs and symptoms

Left: Hand of a person with severe anemia. Right: Hand of a person without anemia.
A patient having thalassemia shows enlarged spleen.
  • Iron overload: People with thalassemia can get an overload of iron in their bodies, either from the disease itself or from frequent blood transfusions. Too much iron can result in damage to the heart, liver, and endocrine system, which includes glands that produce hormones that regulate processes throughout the body. The damage is characterized by excessive deposits of iron. Without adequate iron chelation therapy, almost all patients with beta-thalassemia accumulate potentially fatal iron levels.[16]
  • Infection: People with thalassemia have an increased risk of infection. This is especially true if the spleen has been removed.[17]
  • Bone deformities: Thalassemia can make the bone marrow expand, which causes bones to widen. This can result in abnormal bone structure, especially in the face and skull. Bone marrow expansion also makes bones thin and brittle, increasing the risk of broken bones.[18]
  • Enlarged spleen: The spleen aids in fighting infection and filters unwanted material, such as old or damaged blood cells. Thalassemia is often accompanied by the destruction of a large number of red blood cells and the task of removing these cells causes the spleen to enlarge. Splenomegaly can make anemia worse, and it can reduce the life of transfused red blood cells. Severe enlargement of the spleen may necessitate its removal.[19]
  • Slowed growth rates: anemia can cause the growth of a child to slow down. Puberty may also be delayed in children with thalassemia.[20]
  • Heart problems: Diseases, such as congestive heart failure and abnormal heart rhythms, may be associated with severe thalassemia.[21]

Hemoglobin structural biology

Normal human hemoglobins are tetrameric proteins composed of two pairs of globin chains, each of which contains one alpha-like (α-like) chain and one beta-like (β-like) chain. Each globin chain is associated with an iron-containing heme moiety. Throughout life, the synthesis of the alpha-like and the beta-like (also called non-alpha-like) chains is balanced so that their ratio is relatively constant and there is no excess of either type.[22]

The specific alpha and beta-like chains that are incorporated into Hb are highly regulated during development:

  • Embryonic Hbs are expressed as early as four to six weeks of embryogenesis and disappear around the eighth week of gestation as they are replaced by fetal Hb.[23][24] Embryonic Hbs include:
    • Hb Gower-1, composed of two ζ globins (zeta globins) and two ε globins (epsilon globins) (ζ2ε2)
    • Hb Gower-2, composed of two alpha globins and two epsilon globins (α2ε2)
    • Hb Portland, composed of two zeta globins and two gamma globins (ζ2γ2)
  • Fetal Hb (Hb F) is produced from approximately eight weeks of gestation through birth and constitutes approximately 80 percent of Hb in the full-term neonate. It declines during the first few months of life and, in the normal state, constitutes <1 percent of total Hb by early childhood. Hb F is composed of two alpha globins and two gamma globins (α2γ2). Patients with β-thalassemia exhibit higher levels of gamma globulin, and thus more production of Hb F, to counteract the imbalance from not being able to produce beta chains.[25]
  • Adult Hb (Hb A) is the predominant Hb in children by six months of age and onward; it constitutes 96-97% of total Hb in individuals without a hemoglobinopathy. It is composed of two alpha globins and two beta globins (α2β2).[citation needed]
  • Hb A2 is a minor adult Hb that normally accounts for approximately 2.5-3.5% of total Hb from six months of age onward. It is composed of two alpha globins and two delta globins (α2δ2).[citation needed]

Cause

autosomal recessive
pattern of inheritance.

Both α- and β-thalassemias are often inherited in an

dominantly inherited α- and β-thalassemias have been reported, the first of which was in an Irish family with two deletions of 4 and 11 bp in exon 3 interrupted by an insertion of 5 bp in the β-globin gene. For the autosomal recessive forms of the disease, both parents must be carriers for a child to be affected. If both parents carry a hemoglobinopathy trait, the risk is 25% for each pregnancy for an affected child.[26]

The genes involved in thalassemia control the production of healthy hemoglobin. Hemoglobin binds oxygen in the lungs and releases it when the red cells reach peripheral tissues, such as the liver. The binding and release of oxygen by hemoglobin are essential for survival.[citation needed]

Evolution

Having a single genetic variant for thalassemia may protect against malaria and thus can be an advantage.[27]

People diagnosed with

coronary heart disease.[28]

Pathophysiology

Normally, the majority of adult hemoglobin (

heterotetramer. In thalassemia, patients have defects in either the α or β-globin chain, causing production of abnormal red blood cells.[citation needed
]

The thalassemias are classified according to which chain of the hemoglobin molecule is affected. In

β-thalassemia, production of the β-globin chain is affected.[29]

The β-globin chains are encoded by a single gene on

Africans, but also in Greeks and Turks.[citation needed
]

Alpha-thalassemias

Main article: Alpha-thalassemia

The α-thalassemias involve the genes HBA1

gene loci and so four alleles exist. Two genetic loci exist for α-globin, thus four alleles are in diploid cells. Two alleles are maternal and two alleles are paternal in origin. The severity of the α-thalassemias is correlated with the number of affected α-globin; alleles: the greater, the more severe will be the manifestations of the disease.[33] Alpha-thalassemias result in decreased alpha-globin production; therefore, fewer alpha-globin chains are produced, resulting in an excess of β chains in adults and excess γ chains in newborns. The excess β chains form unstable tetramers (called hemoglobin H or HbH of 4 beta chains), which have abnormal oxygen dissociation curves. Alpha thalassemias often are found in people from Southeast Asia, the Middle East, China, and in those of African descent.[34]

# of missing alleles Types of alpha thalassemia[33] Symptoms
1 Silent carrier No symptoms
2 Alpha thalassemia trait Minor anemia
3 Hemoglobin H disease Mild to moderate anemia; may lead normal life
4 Hydrops fetalis Death usually occurs in utero or at birth

Beta-thalassemia

Main article:
Beta-thalassemia

Beta thalassemias are due to mutations in the

HBB gene on chromosome 11,[35]
also inherited in an autosomal, recessive fashion. The severity of the disease depends on the nature of the mutation and on the presence of mutations in one or both alleles.
Mutated alleles are called β+ when partial function is conserved (either the protein has a reduced function, or it functions normally but is produced in reduced quantity) or βo, when no functioning protein is produced.
The situation of both alleles determines the clinical picture:

  • β thalassemia major (Mediterranean anemia or Cooley anemia) is caused by a βo/βo genotype. No functional β chains are produced, and thus no hemoglobin A can be assembled. This is the most severe form of β-thalassemia;
  • β thalassemia intermedia is caused by a β+/βo or β+/β+ genotype. In this form, some hemoglobin A is produced;
  • β thalassemia minor is caused by a β/βo or β/β+ genotype. Only one of the two β globin alleles contains a mutation, so β chain production is not terribly compromised and patients may be relatively asymptomatic.

Beta thalassemia is more common than alpha variety. Beta type is characterized by a decreas or absence of synthesis of beta chains. As a compensation, gamma or delta-chain synthesis is increased.[36]

Beta thalassemia most often occurs in people of Mediterranean origin. To a lesser extent, Chinese, other Asians, and African Americans can be affected.[34]

Delta-thalassemia

Main article:
Delta-thalassemia

As well as alpha and beta chains present in hemoglobin, about 3% of adult hemoglobin is made of alpha and delta chains. Just as with beta thalassemia, mutations that affect the ability of this gene to produce delta chains can occur.[37][38]

Combination hemoglobinopathies

Thalassemia can coexist with other

hemoglobinopathies
. The most common of these are:

Diagnosis

Thalassemia can be diagnosed via a complete blood count, hemoglobin electrophoresis or high-performance liquid chromatography, and DNA testing.[40][41] Hemoglobin electrophoresis is not widely available in developing countries, but the Mentzer index can also be used for diagnosis of thalassemia; it is not a definitive test but it can suggest the possibility of thalassemia. The Mentzer index can be calculated from a complete blood count report.[42]

Endocrine Complications in Thalassemia

1) Hypogonadism: iron overload in pituitary gonadotropic cells causes decreased gonadotrophin secretion which leads to delayed, slow or arrested puberty.

2) Hypoparathyroidism: chronic anemia causes hematopoiesis which results in bone reabsorption which decreases parathyroid secretion.

3) Adrenal insufficiency: Decreased growth of pubic and axillary hair in adolescent TM patients. This is due to excess iron deposition which causes adrenal dysfunction.

4) Hypothyroidism: Increase in weight and retarded growth in adolescent patients. Secondary is rare and majority suffers from primary hypothyroidism.

[85]

Management

Main article: Management of thalassemia

Given the range of severities, some people require no treatment (those who are asymptomatic) while some people require regular blood transfusions for survival.[43] People with severe thalassemia require medical treatment and the main treatment is usually a red blood cell transfusion.

Red blood cell transfusions

Blood transfusions are the main treatment approach for prolonging life.[44] The approach and frequency needed varies in each person depending on severity, age, if the person has stunted growth, presence of extramedullary erythropoiesis (pediatrics), if a person is pregnant, and heart health. Blood transfusions come with risks including making iron overload worse, the risk of infections, risk of red blood cell antibody formation, increased risk of the development of hypersensitivity reactions, and the risk of gall bladder inflammation (cholecystitis).[43]

Multiple blood transfusions may result in iron overload. The iron overload related to thalassemia may be treated by chelation therapy with the medications deferoxamine, deferiprone, or deferasirox.[45][46][47] These treatments have resulted in longer life expectancy for those with thalassemia major.[45] Deferoxamine is only effective as a daily injection, complicating its long-term use. However, it is inexpensive and safe. Adverse effects include primary skin reactions around the injection site and hearing loss.[45] Deferasirox and deferiprone are both oral medications, whose common side effects include nausea, vomiting and diarrhea. When comparing effectiveness, there is no evidence that deferasirox or deferiprone is superior, however, a long term comparison has not been performed.[47] Deferasirox is not effective for all patients and may not be suitable for those with significant cardiac issues related to iron overload, while deferiprone appears to be the most effective agent when the heart is involved. Furthermore, the cost of deferasirox is also significant.[45] Combining calcium channel blocker medications with iron chelation therapy is under study, however, the benefits are not clear from clinical trials conducted.[48]

Growth hormone therapy

There is some evidence that growth hormone replacement therapy may help to increase the rate at which children with thalassemia grow taller.[49]

Bone-marrow transplantation

non-identical donor bone-marrow transplantation in persons with β- thalassemia who are dependent on blood transfusion.[52]

Graft-versus-host diseases (GvHD) are one relevant side effect of bone-marrow transplantation. Further research is necessary to evaluate whether mesenchymal stromal cells can be used as prophylaxis or treatment for GvHD.[53]

If the person does not have an HLA-matched compatible donor, bone-marrow transplantation from haploidentical mother to child (mismatched donor) may be attempted. In a study of 31 people, the thalassemia-free survival rate was 70%, rejection 23% and mortality 7%. The most positive results tend to occur with very young people.[54]

Other treatments

Many treatments are being investigated with the goal of reducing the number of blood transfusions that a person requires.

Hydroxyurea treatment with the goal of reactivating gamma‐genes to produce HbF also does not have any high quality evidence supporting its effectiveness.[55]

There is no evidence from randomized controlled trials to support zinc supplementation for those with thalassemia.[56] Computer programs or mobile applications have been suggested as tools to help people manage thalassemia and follow their therapies including iron chelation therapy. The effectiveness of these applications has not been well investigated.[57]

People with thalassemia are at a higher risk of osteoporosis.[58] Treatment options include bisphosphonates and sometimes the addition of hormonal therapy. Other treatments have been suggested including calcitonin, zinc, hydroxyurea, and calcium supplementation. The effectiveness of bisphosphonates and zinc is not clear and further studies are required.[58]

Dental care

Helping people with thalassemia with dental care and treating dental problems can be challenging due to the underlying condition. Overload of iron due to blood transfusions may lead to iron deposition in the teeth and discolouration, and there is an increased risk for infection.[59] Treatment options for people with thalassemia need to be modified to ensure that the needs of the person are considered and early detection and early management of any problems is strongly suggested in order to reduce the risk of the person needing more complicated dental treatments.[59] The evidence supporting the effectiveness of dental treatments on people with thalassemia is weak and higher quality clinical trials are needed.[59]

Mild thalassemia

People with thalassemia

iron supplements, but iron deficiency may develop during pregnancy or from chronic bleeding.[60] Genetic counseling is indicated for all persons with genetic disorders, especially when the family is at risk of a severe form of disease that may be prevented.[61]

Prevention

The American College of Obstetricians and Gynecologists recommends all people thinking of becoming pregnant be tested to see if they have thalassemia.[62] Genetic counseling and genetic testing are recommended for families who carry a thalassemia trait.[26] Understanding the genetic risk, ideally before a family is started, would hopefully allow families to understand more about the condition and make an informed decision that is best for their family.[26]

A screening policy exists in Cyprus to reduce the rate of thalassemia, which, since the program's implementation in the 1970s (also including prenatal screening and abortion), has reduced the number of children born with the disease from one of every 158 births to almost zero.[63] Greece also has a screening program to identify people who are carriers.[64]

In Iran as a premarital screening, the man's red cell indices are checked first. If he has microcytosis (mean cell hemoglobin < 27 pg or mean red cell volume < 80 fl), the woman is tested. When both are microcytic, their hemoglobin A2 concentrations are measured. If both have a concentration above 3.5% (diagnostic of thalassemia trait) they are referred to the local designated health post for genetic counseling.[65]

Large-scale awareness campaigns are being organized in India[66] both by government and non-government organizations to promote voluntary premarital screening, with marriage between carriers strongly discouraged.

Epidemiology

The beta form of thalassemia is particularly prevalent among

Mediterranean peoples, and this geographical association is responsible for its original name.[67] Thalassemia resulted in 25,000 deaths in 2013 down from 36,000 deaths in 1990.[14]

In Europe, the highest concentrations of the disease are found in

South Asians are also affected, with the world's highest concentration of carriers (16–18% of the population) in the Maldives.[68]

The disease is also found in populations living in Africa, the Americas, and in

Palestinians and people of Palestinian descent), and Asians.[71] The estimated prevalence is 16% in people from Cyprus, 1%[72] in Thailand, and 3–8% in populations from Bangladesh, China, India, Malaysia and Pakistan
.

Estimates suggest that approximately 1.5% of the global population (80 – 90 million people) are β-thalassemia carriers.[73] However, exact data on carrier rates in many populations are lacking, particularly in developing areas of the world known or expected to be heavily affected.[74][75] Because of the prevalence of the disease in countries with little knowledge of thalassemia, access to proper treatment and diagnosis can be difficult.[76] While there are some diagnostic and treatment facilities in developing countries, in most cases these are not provided by government services and are available only to patients who can afford them. In general, poorer populations only have access to limited diagnostic facilities and blood transfusions. In some developing countries, there are virtually no facilities for diagnosis or management of thalassemia.[76]

Etymology and synonym

The word thalassemia (

thalassa (θάλασσα), "sea",[77] and Neo-Latin -emia (from the Greek compound stem -aimia (-αιμία), from haima (αἷμα), "blood").[78] It was coined because the condition called "Mediterranean anemia" was first described in people of Mediterranean ethnicities. "Mediterranean anemia" was renamed thalassemia major once the genetics were better understood. The word thalassemia was first used in 1932.[67]: 877 [79]



Research

Gene therapy

lentiviral vector. After destroying the affected person's bone marrow with a dose of chemotherapy (a myeloablative conditioning regimen), the altered HSCs are infused back into the affected person where they become engrafted in the bone marrow where they proliferate. This potentially results in a progressive increase in hemoglobin A2 synthesis in all subsequent developing red blood cells, with resultant resolution of the anemia.[81]

While one person with beta thalassemia has no longer required blood transfusions following treatment within a research trial, it is not an approved treatment as of 2018.[80][82]

HbF induction

HbF induction is an attempt to reactivate fetal globin gene transcription.[83] Efforts involve trying to disrupt the fetal globin gene promoter.[83]

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External links

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