Sideroblastic anemia is an acquired or hereditary blood disease characterized by hypochromia of erythrocytes, high levels of serum iron with deposition in the tissues of organs. The clinical picture is represented by anemic syndrome (dizziness, fatigue, pallor of the skin), hemosiderosis of internal organs (hepatomegaly, cardiomegaly, CRF), a change in the blood picture. The diagnosis is made on the basis of clinical and biochemical analyses (blood test, serum Fe, ferritin, transferrin, vitamin B6), genodiagnostics, myelogram studies. Treatment may include blood transfusions, vitamin and hormone therapy, chelation therapy.
ICD 10
D64.0 D64.1 D64.2 D64.3
Meaning
Sideroblastic (sideroachrestic) anemia includes several heterogeneous syndromes that occur with a violation of heme synthesis, despite the increased iron content in plasma. The population frequency of sideroblastic anemia (SBA) has not been clarified due to their clinical heterogeneity, however, it is known that acquired forms are more common than hereditary ones. Congenital anemia usually manifests in childhood, but may remain unrecognized until adulthood. Primary acquired sideroblastic anemia is diagnosed mainly in middle-aged and elderly people.
Sideroblastic anemia causes
Congenital sideroblastic anemia
Congenital SBA are associated with mutations in the genetic material. They differ in the type of inheritance and pathogenetic mechanism:
- X-linked sideroblastic anemia. One variant is caused by defects in the type II delta‒aminolevulenic acid ALAS2 synthase gene (locus Xp11.21). Another type of disease is associated with transgenations of hABC7 (Xp13.1-q13.3) encoding a protein involved in heme transport.
- Autosomal recessive sideroblastic anemia. A genetically heterogeneous group. It may occur with a defect in the WFS1 (4p16.1) gene responsible for the expression of the transmembrane protein wolframin. In this case, SBA is diagnosed as part of the Wolfram syndrome (DIDMOAD). Another form develops with defects in the SLC25A38 gene encoding the glycine transporter protein necessary for heme synthesis.
- Mitochondrial cytopathy. Caused by mitochondrial DNA deletions, clinically manifested by the development of Pearson’s syndrome.
- Sporadic sideroblastic anemia. Caused by the appearance of newly arisen genetic mutations that are absent from parents and other family members.
Acquired sideroblastic anemia
Idiopathic (primary) SBA ‒ refractory anemia with annular sideroblasts ‒ are considered as a type of myelodysplastic syndrome (MDS) and occupy 5-15% in its structure. More often they occur as a consequence of radiation or cytostatic therapy carried out for collagenoses, hemoblastoses, various oncological processes. The risk of developing MDS is increased in smokers, persons in contact with chemicals (gasoline, solvents, insecticides).
Secondary sideroblastic anemia may be etiologically related to the following factors:
- taking antibacterial and tuberculostatic drugs (chloramphenicol, linezolid, isoniazid, cycloserine);
- lead intoxication;
- chronic alcoholism;
- violation of the balance of vitamins and trace elements: pyridoxine deficiency (vitamin B6), lack of copper, excess zinc;
- collagenoses;
- blood diseases (polycythemia, hemolytic anemia).
Pathogenesis
Regardless of the variety of causes, all of them in one way or another lead to a violation of heme formation. Heme is a compound consisting of protoporphyrin and an iron atom (Fe2+). When it binds to the protein globin, heme-containing chromoprotein hemoglobin is formed, whose main function is to transport oxygen to tissues, and carbon dioxide from tissues.
With SBA, as a result of defects in enzyme systems, pyridoxal phosphate deficiency, toxic effects or other factors, protoporphyrin biosynthesis is disrupted, which makes heme formation impossible, despite a sufficient level of Fe in the blood serum. Hypochromic anemia develops. In conditions when iron is not used by cells, it begins to accumulate in tissues and internal organs with the development of their dysfunction.
Classification
Sideroblastic anemia is divided into 2 large groups – hereditary and acquired, within which specific clinical forms associated with certain etiofactors are distinguished:
1. Hereditary sideroblastic anemia:
- X-linked;
- autosomal (may be pyridoxine-refractory and pyridoxine-dependent);
- mitochondrial diseases.
2. Acquired sideroblastic anemia:
- primary ‒ clonal SBA in the framework of myelodysplastic syndrome;
- secondary ‒ reversible SBA (medicinal, toxic, alimentary);
- against the background of other diseases (systemic, hematological, etc.)
Sideroblastic anemia symptoms
Two groups of symptoms predominate in the clinical picture of sideroachrestic anemia: circulatory hypoxic and organ failure due to hemosiderosis. Hematological changes are detected during diagnostic examination of blood and bone marrow.
Hypoxic syndrome is accompanied by malaise and weakness, tachycardia, a decrease in blood pressure. Complaints of dizziness, aching pains in the heart, the appearance of “flies” in front of the eyes, shortness of breath during movements are characteristic. There is dryness and pallor of the skin, brittle nails. Children’s memorization of educational material worsens, academic performance decreases.
Iron deposition leads to the development of hepatosplenomegaly, and in the later stages – cirrhosis of the liver. The defeat of the pancreas is accompanied by the manifestation of diabetes mellitus. Myocardial hemosiderosis is manifested by cardiomegaly, rhythm disturbance, heart failure. The deposition of iron in the tissues of the male sex glands causes secondary hypogonadism. When the lungs are affected, respiratory failure occurs, and chronic renal failure.
Complications
Iron overload causes irreversible organ damage, leading to persistent functional insufficiency of the heart, liver, kidneys, and endocrine organs. Such patients require lifelong replacement and maintenance therapy, their overall life expectancy is reduced. The course of the idiopathic form of sideroblastic anemia in 5-10% of patients is complicated by acute leukemia, refractory to polychemotherapy.
Diagnostics
The basis for the diagnosis of “sideroblastic anemia” is clinical and laboratory data. Patients are advised by a hematologist, if necessary – a geneticist, toxicologist, rheumatologist, narcologist. The basic diagnostic criteria are:
- Hemogram. Characteristic changes in peripheral blood include a decrease in Hb and CP, possible reticulocytopenia. Basophilic granularity of erythrocytes, Pappenheimer’s corpuscles is detected in the blood smear. Erythrocytes are often reduced in size (microcytic anemia), have an abnormal shape.
- Biochemical research. Serum iron, ferritin and transferrin levels are elevated, CBV is reduced. There is indirect hyperbilirubinemia, an increase in LDH. Vitamin B6 deficiency may be detected. In case of toxic SBA, a study of the lead content in the blood is shown.
- Genodiagnostics. It is carried out if a hereditary form of sideroblastic anemia is suspected. The diagnosis is considered reliable when mutations in causal genes are detected.
- Urine examination. The study of porphyrins in daily urine shows their increased excretion. The results of the desferal test demonstrate the excretion of a significant amount of iron in the urine.
- Myelogram. The cytological picture of the bone marrow punctate indicates hyperplasia of the erythroid germ of myelopoiesis. More than 40% of erythrocyte precursors are represented by ring-shaped sideroblasts.
- Biopsy of internal organs. During liver biopsy, iron deposits are found in hepatocytes, sometimes signs of cirrhosis. It is possible to conduct a biopsy of the spleen, pancreas.
Sideroblastic anemia treatment
With toxic and medicinal forms of SBA, the provoking factor is primarily eliminated (drugs are canceled, detoxification therapy is carried out, etc.). Drug therapy of sideroblastic anemia includes the appointment of the following drugs:
- Vitamin B6. Pyridoxine-dependent forms (some hereditary, alimentary, alcoholic) are amenable to pyridoxine hydrochloride or pyridoxal phosphate therapy. With a positive response, long courses are carried out with large doses of vit. B6 followed by supportive vitamin therapy.
- Hormone therapy. It is indicated for patients with pyridoxine-resistant form of sideroblastic anemia. Anabolic hormones, androgens, erythropoietin are prescribed.
- Chelation therapy. The introduction of deferoxamine is aimed at removing excess iron from the body, reducing the severity of hemosiderosis. Phlebotomy can also be used to correct iron overload.
- Auxiliary therapy. It includes the appointment of folic acid, antioxidants (vit. E, lipoic acid), hepatoprotectors.
With severe anemia syndrome, there is a need for blood transfusions. In case of a significant enlargement of the spleen, splenectomy is performed. There are separate reports in the literature on the effectiveness of allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of hereditary pyridoxine-resistant sideroblastic anemia.
Prognosis and prevention
The prognosis for sideroblastic anemia is due to its etiology. Pyridoxine-dependent and some acquired forms (medicinal, alimentary) are better amenable to correction. Significantly reduced life expectancy in people with SBA, transfusion-dependent, refractory to treatment, associated with leukemia, Pearson syndrome. Prevention, first of all, concerns secondary sideroblastic anemia: you should eat well, take vitamin complexes, avoid intoxication (ethanol, lead) and contact with harmful substances. Genetic counseling is recommended to exclude hereditary SBA.
Literature
- Sheftel AD, Richardson DR, Prchal J, Ponka P. Mitochondrial iron metabolism and sideroblastic anemia. Acta Haematol. 2009;122(2-3):120-33. – link
- Camaschella C. Hereditary sideroblastic anemias: pathophysiology, diagnosis, and treatment. Semin Hematol. 2009 Oct;46(4):371-7. –
- Fitzsimons EJ, May A. The molecular basis of the sideroblastic anemias. Curr Opin Hematol. 1996 Mar;3(2):167-72. – link
- Massey AC. Microcytic anemia. Differential diagnosis and management of iron deficiency anemia. Med Clin North Am. 1992 May;76(3):549-66. – link
- Severance S, Hamza I. Trafficking of heme and porphyrins in metazoa. Chem Rev. 2009 Oct;109(10):4596-616. – link