Thalassemia

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Classification according to ICD-10
D56.0 Alpha thalassemia
D56.1 Beta thalassemia
D56.2 Delta beta thalassemia
D56.3 Thalassemia minor (hereditary disposition / trait)
D56.4 Hereditary Persistence of Fetal Hemoglobin (HPFH)
D56.8 Other thalassemias
D56.9 Thalassemia, unspecified
D57.2 Sickle cell thalassemia
ICD-10 online (WHO version 2019)

As thalassemia or Mediterranean anemia diseases of red blood cells refers to, in which a genetic defect by the hemoglobin is not degraded sufficiently formed or increased.

Gene defects on chromosome 11 (in β-thalassemia) or 16 (in α-thalassemia), which lead to reduced globin chain formation, are responsible for the development of thalassemia. The different thalassemia variants are named after the globins that are not produced in sufficient quantities: α- and β-thalassemia. Most mutations are inherited in an autosomal recessive manner and occur mainly in former malaria areas in the Mediterranean (Malta, Sardinia, Sicily, Greece, Cyprus, Turkey), in the Middle East and among the population of African descent. The hereditary disease is particularly common in Cyprus, where it is fought intensively through diagnostics and genetic selection (abortion) ( prevention of thalassemia in Cyprus ).

β-thalassemia

Β-thalassemia is the most common form of thalassemia. More than 4000 mutations are known from her , which usually make up smaller grid or point mutations at the β-globin locus and only rarely make up longer deletions. Most β-thalassemia mutations are inherited as an autosomal recessive trait. Β-thalassemia is divided into two forms, thalassemia minor and thalassemia major.

Genetics of β-thalassemia

Β-thalassemia is caused by mutations in DNA sequences that are necessary for the correct splicing of the primary β-globin transcript . This consists of three exons and two introns . Mutations in the recognition sequences lead to various aberrant splicing patterns, examples are:

  • Skipping exon 2 as the necessary recognition sequence is lost.
  • The activation of a cryptic splicing site (i.e. sequences that resemble real splicing sites) and thus the creation of an abnormally elongated exon 3 or
  • The emergence of new splicing signals in intron sequences that lead to additional exons.

Thalassemia minor - heterozygous form (Rietti-Greppi-Micheli syndrome)

The heterozygous mutation carriers usually show no clinical symptoms, since the defect is recessive compared to the healthy allele . However, there may be a slightly enlarged spleen. This form of thalassemia therefore does not require any therapy.

Thalassemia major - homozygous form (so-called Cooley anemia)

In Cooley's anemia, the β-globin chains are not formed at all, which means that normal HbA1 (α2β2) cannot be produced. The large excess of γ- and δ-globins leads to defective, unstable erythrocytes which perish again in the bone marrow (ineffective erythropoiesis ).

The homozygous mutation carriers are seriously ill because both alleles are affected. The patients have a greatly enlarged liver and spleen just a few months after birth, and later suffer from growth disorders, severe damage to internal organs and bone malformations.

The main symptom is severe anemia . It is defined as a pathologically reduced hemoglobin concentration in the blood resulting in a lifelong need for transfusion of the patient, which, if left untreated, leads to death in early childhood. Typically, patients receive blood transfusions every two to six weeks to make up for the hemoglobin deficiency. The bone marrow tries to compensate for the lack of functioning hemoglobin caused by the ineffective erythropoiesis by overproducing it. This creates compensatory hypertrophies , which are typically particularly pronounced in the cheek and skullcap bones (widened cheekbones, wide eye relief and the so-called brush skull on the X-ray ). The spleen now increasingly filters the defective erythrocytes from the blood and breaks them down. The heavy use of the spleen leads to splenomegaly. The concentration of bilirubin , a decomposition product of the erythrocytes, increases in the blood. Usually the bilirubin is broken down in the liver. However, if the level of bilirubin in the blood is very high, jaundice occurs . The lack of oxygen results in cardiac stress, which means that the heart tries to compensate for the lack of oxygen with a higher pumping frequency and is thus additionally stressed.

In addition to lifelong transfusion dependency, the development of iron overload ( hemosiderosis ), which is predominantly therapy- related, is the most serious problem of all patients with homozygous β-thalassemia. Normally the iron content of humans is around 4 g. Healthy people consume around 1 mg daily. One milliliter of a blood unit contains approx. 1 mg iron . With an average transfusion requirement of 200 ml / kg body weight / year, a patient who weighs about 30 kg is therefore supplied with about 6 g of iron every year. The resulting increased iron poisoning of the body leads to severe organ damage in the area of ​​the heart, liver and pancreas.

α-thalassemia

The rarer variant is α-thalassemia. The lack of α chains results in an excess of γ and β globins. The most common mutation in α-thalassemia is caused by a deletion with unequal crossing over during meiosis . A total of about 55 mutations are known, most of which are point mutations and are inherited as an autosomal recessive trait. The clinical picture is determined by the number of α-genes still functioning. In the most severe form, the inactivation of all four α genes, the embryo dies in the uterus. If three genes are inactive, it is known as HbH disease, which is characterized by a milder form of thalassemia. Overall, patients with HbH disease show hardly any external symptoms, since HbA molecules can still be formed. As a result, patients with HbH disease rarely need blood transfusions.

diagnosis

The blood count (normal or even elevated serum iron, hypochromic and microcytic red blood cells) can indicate the presence of this disease. Increased erythrocyte counts are also often due to thalassemia. So - called target cells (erythrocytes colored like a target ) can typically be found in the microscope . The diagnosis is based on the symptoms detected and by means of a Hb - electrophoresis secured. Molecular genetic evidence of the mutations allows prenatal diagnosis if the partner also has thalassemia minor (or major).

therapy

In the case of homozygosity in the sense of thalassemia major, symptomatic therapy with regular blood transfusions (so-called hypertransfusion regime) takes place first . This approach means that every 2-4 weeks 1-3 blood products ( packed red blood cells are transfused) the affected patients. The aim is to suppress the ineffective blood formation caused by thalassemia major , which, if left untreated, leads to severe hemolytic anemia. The splenectomy , which was carried out regularly years ago, is now only used cautiously or as late as possible, as there is a risk of serious bacterial infections after the spleen has been removed ( post- splenectomy syndrome , OPSI = Overwhelming Post Splenectomy Infection Syndrome ). An indication for splenectomy is, for example, insufficient response to regular transfusions due to the destruction of the red blood cells in the spleen.

The hypertransfusion regimen is able to excellently suppress the effects of thalassemia major on skeletal development and on the size of the liver and spleen as sites of additional blood formation. It is disadvantageous that the amount of iron supplied by means of the blood reserves is greater than the amount of iron that the body can excrete. As a result, iron is deposited in the liver, heart ( myocardium ), pancreas ( pancreas ) and the pituitary gland ( pituitary gland ). This is known as secondary hemosiderosis. The iron deposition leads to an increasing loss of function of the affected organs. Heart muscle weakness results in the heart , severe hormonal disorders in the pituitary gland with a lack of growth, sexual development, hypothyroidism, etc., and diabetes mellitus in the pancreas due to the destruction of the insulin-producing cells.

Therefore, iron-releasing therapy (chelation) is a quasi-mandatory accompanying treatment for thalassemia, which is treated with a hypertransfusion regime. Here, substances are administered parenterally (infusion) or orally (tablet or capsule) that cause increased iron excretion. Active substances here are deferoxamine as well as deferasirox and deferiprone .

Both the hypertransfusion regimen and chelation must be carried out for life.

The only curative (healing) form of treatment for thalassemia major consists in carrying out a stem cell transplant with hematopoietic stem cells or bone marrow from a related or unrelated donor. The stem cell transplant replaces the defective formation of red blood cells after the original bone marrow has been destroyed by radiation or chemotherapy. However, due to the necessary destruction of the original bone marrow and the resulting temporary consequences such as immune deficiency, risk of bleeding and anemia, this treatment is full of complications, but it is the only chance of a complete cure. It is possible to replace the bone marrow of a thalassemia major patient with bone marrow of a thalassemia minor patient.

As a rule, thalassemia minor does not require any treatment. Only during pregnancy in affected women can the anemia reach proportions that require treatment. Otherwise, a normal life is possible with thalassemia minor.

Complications

  • Hemosiderosis . Since humans do not have iron elimination mechanisms, patients from around 2–4 years of age must take medication every day for life. These drugs form complexes with the iron in the body and lead to an increased excretion of iron and thus an improvement in the iron balance. While this used to have to be carried out as a so-called iron chelate therapy in the form of a nightly infusion, preparations are now available that can be taken as tablets / capsules. The iron chelators include the following active ingredients: Desferoxamine (parenteral only), Deferiprone (L1) and Deferasirox (ICL-670).
  • Heart failure : Thanks to this therapy, heart failure, which used to be a life-limiting factor between the ages of 25 and 30, can now be avoided.
  • Liver insufficiency : The liver insufficiency (liver damage) results from the iron deposition in the liver tissue in the context of hemosiderosis. The detection of hepatosiderosis (iron deposition in the liver) can be carried out either by a liver biopsy with subsequent Berlin blue staining of the removed tissue or by means of SQUID (SQUID) or by means of a special form of magnetic resonance imaging (MRT).
  • Diabetes mellitus
  • Growth disorders and skeletal changes. Regular blood transfusions can get most problems under control. The oxygen transport is improved and an increased erythropoiesis is reduced. This also prevents compensatory hypertrophies and the associated skeletal changes.
  • Hair loss

history

The first description of β-thalassemia is a work by the US pediatrician Thomas B. Cooley , A Series of Cases of Splenomegaly in Children, with Anemia and Peculiar Bone Changes , from 1925. In 1932, Whipple and Bradford first used the term Thalassemia used, and six years later the Greek doctor Caminopetros published the thesis that thalassemia is hereditary, and shortly afterwards the complete amino acid sequences for the various hemoglobin chains were determined. It later became clear that thalassemia is a heterogeneous group of hereditary diseases that do not only occur in the Mediterranean region. With the discovery of the enzyme reverse transcriptase it was finally possible to examine the mRNA of thalassemia patients and thus to recognize that the diseases are based on a reduced production of mRNA, which is necessary for globin production.

malaria

Thalassemia was evolutionarily favored by malaria: the deformation of the red blood cells causes shortness of breath, but at the same time it slows down the pathogens that cause malaria. People with thalassemia are specially protected from the deadly anemia caused by malaria infection. This was also confirmed in a study with over 2,500 children with life-threatening illnesses. Due to the short lifespan of the red blood cells, the body tries to increase the number of cells by multiplying new ones. During a malaria attack, the number of red blood cells decreases by 30 to 50 percent. But many children with the mild form of the blood disease could not be affected by this loss, because their thalassemia had previously had 10 to 20 percent more red blood cells than children without the genetic defect. It is therefore no coincidence that thalassemia occurs primarily in former malaria areas such as Malta, Sardinia, Greece, Cyprus, Israel and even Iran. However, patients with thalassemia are not generally immune to malaria pathogens. In the absence of treatment, malaria can therefore be fatal even with thalassemia.

literature

  • Alberts et al: Molecular Biology of the Cell. 5th edition. Garland Science, pp. 354-355.
  • H. Cario, K. Stahnke, S. Sander, E. Kohne: Epidemiological situation and treatment of patients with thalassemia major in Germany: results of the German multicenter beta-thalassemia study. In: Ann Hematol. 2000; 79 (1), pp. 7-12.
  • H. Cario, K. Stahnke, E. Kohne: Beta-thalassemia in Germany. Results of cooperative beta-thalassemia study. In: Klin Padiatr. 1999; 211 (6), pp. 431-437.
  • P. Mazza, R. Giua, S. De Marco et al .: Iron overload in thalassemia: comparative analysis of magnetic resonance imaging, serum ferritin and iron content of the liver. In: Haematologica . 1995; 80 (5), pp. 398-404.
  • T. Gungor, E. Rohrbach, E. Solem, JP Kaltwasser, B. Kornhuber: Logarithmic quantitation model using serum ferritin to estimate iron overload in secondary haemochromatosis. In: Arch Dis Child . 1996; 74 (4), pp. 323-327.
  • D. Gaziev, C. Giardini, E. Angelucci et al .: Intravenous chelation therapy during transplantation for thalassemia. In: Haematologica. 1995; 80 (4), pp. 300-304.
  • PJ Giardina, RW Grady: Chelation therapy in beta-thalassemia: the benefits and limitations of desferrioxamine. In: Semin Hematol. 1995; 32 (4), pp. 304-312.
  • R. Naithani, J. Chandra, S. Sharma: Safety of oral iron chelator deferiprone in young thalassaemics. In: Eur J Haematol. 2005; 74 (3), pp. 217-220.
  • A. Maggio, G. D'Amico, A. Morabito: Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial. In: Blood Cells Mol Dis. 2004; 32 (1), pp. 141-142.
  • MD Cappellini, A. Cohen, A. Piga et al .: A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. In: Blood . 2006; 107 (9), pp. 3455-3462.
  • R. Gibson: Alpha thalassemia-mental retardation, X linked. In: Orphanet Journal of Rare Diseases. 1, 2006, 15. doi: 10.1186 / 1750-1172-1-15 (Review, Open Access )

Web links

Individual evidence

  1. C. Schwarz-Muche: Molecular characterization of β-thalassemia in subjects of German origin. Dissertation . Medical Faculty Charité at Humboldt University Berlin, 1998.
  2. ^ Journal of the American Medical Association. JAMA 2007, 297, pp. 2220-2226.
  3. Thomas Schmidt: Only barely survived: Malaria patient complains after flu diagnosis . In: sueddeutsche.de . ISSN  0174-4917 ( sueddeutsche.de [accessed March 7, 2017]).