Sideroblastic anemia

Sideroblastic anemia
A Ring Sideroblast visualized by Prussian blue stain
Classification and external resources
ICD-10	D64.0-D64.3
ICD-9	285.0
OMIM	301310 206000 300751
DiseasesDB	12110
MeSH	D000756

Sideroblastic anemia or sideroachrestic anemia is a form of anemia in which the bone marrow produces ringed sideroblasts rather than healthy red blood cells (erythrocytes).^[1] It may be caused either by a genetic disorder or indirectly as part of myelodysplastic syndrome,^[2] which can evolve into hematological malignancies (especially acute myelogenous leukemia). In sideroblastic anemia, the body has iron available but cannot incorporate it into hemoglobin, which red blood cells need to transport oxygen efficiently.

Sideroblasts (sidero- + -blast) are atypical, abnormal nucleated erythroblasts (precursors to mature red blood cells) with granules of iron accumulated in perinuclear mitochondria.^[3] Normally, Sideroblasts are present in the bone marrow, and enter the circulation after maturing into a normal erythrocyte.

Ring sideroblasts are named so because of the arrangement of the iron granules in a ring form in mitochondria around the nucleus. However, the ring need not be complete in order to count a cell as a ring sideroblast. According to the 2008 WHO classification of the tumors of the hematopoietic and lymphoid tissues, it only needs 5 or more iron granules encircling one third or more of the nucleus.^[4]

The WHO International Working Group on Morphology of MDS (IWGM-MDS) defined three types of sideroblasts:

1. Type 1 sideroblasts: fewer than 5 siderotic granules in the cytoplasm
2. Type 2 sideroblasts: 5 or more siderotic granules, but not in a perinuclear distribution
3. Type 3 or ring sideroblasts: 5 or more granules in a perinuclear position, surrounding the nucleus or encompassing at least one third of the nuclear circumference.

Classification

Sideroblastic anemia is typically divided into subtypes based on its cause.

• Hereditary or congenital sideroblastic anemia may be X-linked^[5] or autosomal.

OMIM	Name	Gene
300751	X-linked sideroblastic anemia (XLSA)	ALAS2
301310	sideroblastic anemia with spinocerebellar ataxia (ASAT)	ABCB7
205950	pyridoxine-refractory autosomal recessive sideroblastic anemia	SLC25A38
206000	pyridoxine-responsive sideroblastic anemia	(vitamin B6 deficiency; pyridoxal phosphate required for heme synthesis)

GLRX5 has also been implicated.^[6]

• Acquired, or secondary, sideroblastic anemia develops after birth and is divided according to its cause.

Symptoms

Symptoms of sideroblastic anemia include skin paleness, fatigue, dizziness, and enlarged spleen and liver. Heart disease, liver damage, and kidney failure can result from iron buildup in these organs.^[7]

Causes

Causes of sideroblastic anemia can be categorized into three groups: congenital sideroblastic anemia, acquired clonal sideroblastic anemia, and acquired reversible sideroblastic anemia. All cases involve dysfunctional heme synthesis or processing. This leads to granular deposition of iron in the mitochondria that form a ring around the nucleus of the developing red blood cell. Congenital forms often present with normocytic or microcytic anemia while acquired forms of sideroblastic anemia are often normocytic or macrocytic.

• Congenital sideroblastic anemia
  • X-linked sideroblastic anemia: This is the most common congenital cause of sideroblastic anemia and involves a defect in ALAS2,^[8] which is involved in the first step of heme synthesis. Although X-linked, approximately one third of patients are women due to skewed X-inactivation.
  • Autosomal recessive sideroblastic anemia involves mutations in the SLC25A38 gene. The function of this protein is not fully understood, but it is involved in mitochondrial transport of glycine. Glycine is a substrate for ALAS2 and necessary for heme synthesis. The autosomal recessive form is typically severe in presentation.
  • Genetic syndromes: Rarely, sideroblastic anemia may be part of a congenital syndrome and present with associated findings, such as ataxia, myopathy, and pancreatic insufficiency.
• Acquired clonal sideroblastic anemia
  • Clonal sideroblastic anemias fall under the broader category of myelodysplastic syndromes (MDS). Three forms exist and include refractory anemia with ringed sideroblasts (RARS), refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T), and refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS). These anemias are associated with increased risk for leukemic evolution.
• Acquired reversible sideroblastic anemia
  • Causes include excessive alcohol use (the most common cause of sideroblastic anemia), pyridoxine deficiency, lead poisoning, and copper deficiency. Excess zinc can indirectly cause sideroblastic anemia by decreasing absorption and increasing excretion of copper. Antimicrobials that may lead to sideroblastic anemia include isoniazid, chloramphenicol, cycloserine, and linezolid.^[9]

Diagnosis

Ringed sideroblasts are seen in the bone marrow.

The anemia is moderate to severe and dimorphic with marked anisocytosis and poikilocytosis. Basophilic stippling is marked and target cells are common. Pappenheimer bodies are present. The MCV is commonly decreased (i.e., a microcytic anemia), but MCV may also be normal or even high. The RDW is increased with the red blood cell histogram shifted to the left. Leukocytes and platelets are normal. Bone marrow shows erythroid hyperplasia with a maturation arrest.

In excess of 40% of the developing erythrocytes are ringed sideroblasts. Serum iron, percentage saturation and ferritin are increased. The TIBC is normal to decreased. Stainable marrow hemosiderin is increased.

Laboratory findings

• Serum Iron: High
• Increased ferritin levels
• Normal total iron-binding capacity
• High transferrin saturation
• Hematocrit of about 20-30%
• The mean corpuscular volume or MCV is usually normal or low for congenital causes of sideroblastic anemia but normal or high for acquired forms.
• With lead poisoning, see coarse basophilic stippling of red blood cells on peripheral blood smear
• Specific test: Prussian blue stain of RBC in marrow shows ringed sideroblasts. Prussian blue staining involves a non-enzymatic reaction of ferrous iron with ferrocyanide forming ferric-ferrocyanide, which is blue in color. A counterstain may be used to provide better visualization.

Treatment

Occasionally, the anemia is so severe that support with transfusion is required. These patients usually do not respond to erythropoietin therapy.^[10] Some cases have been reported that the anemia is reversed or heme level is improved through use of moderate to high doses of pyrodoxine (Vitamin B₆). In severe cases of SBA, bone marrow transplant is also an option with limited information about the success rate. Some cases are listed on MedLine and various other medical sites. In the case of isoniazid-induced sideroblastic anemia, the addition of B₆ is sufficient to correct the anemia. Desferrioxamine, a chelating agent, is used to treat iron overload from transfusions. Therapeutic phlebotomy can be used to manage iron overload.^[11] Bone marrow transplant (BMT) can be considered in severe cases.

Course and prognosis

Sideroblastic anemias are often described as responsive or non-responsive in terms of increased hemoglobin levels to pharmacological doses of vitamin B₆.

1- Congenital: 80% are responsive, though the anemia does not completely resolve.

2- Acquired clonal: 40% are responsive, but the response may be minimal.

3- Acquired reversible: 60% are responsive, but course depends on treatment of the underlying cause.

Severe refractory sideroblastic anemias requiring regular transfusions and/or that undergo leukemic transformation (5-10%) significantly reduce life expectancy.

See also

• Anemia
• Siderosis
• List of hematologic conditions
• Hematopoietic stem cell transplantation

References

External links

• GeneReviews/NCBI/NIH/UW entry on X-Linked Sideroblastic Anemia and Ataxia
• Sideroblastic Anemias: Introduction - Information Center for Sickle Cell and Thalassemic Disorders
• A concise description of this group of diseases from the Iron Disorders Institute
• Anemia, Sideroblastic at NIH's Office of Rare Diseases
• Sideroblastic Anemias Information Center
• Rare Anemias Foundation

Diseases of RBCs and megakaryocytes / MEP (D50–69,74, 280–287) Red blood cells ↑ Poly- cythemia Polycythemia vera ↓ Anemia Nutritional Micro-: Iron-deficiency anemia Plummer–Vinson syndrome Macro-: Megaloblastic anemia Pernicious anemia Hemolytic (mostly normo-) Hereditary enzymopathy: G6PD glycolysis PK TI HK hemoglobinopathy: Thalassemia alpha beta delta Sickle-cell disease/trait HPFH membrane: Hereditary spherocytosis Minkowski–Chauffard syndrome Hereditary elliptocytosis Southeast Asian ovalocytosis Hereditary stomatocytosis Acquired Autoimmune WAHA CAD PCH membrane PNH MAHA TM HUS Drug-induced autoimmune Drug-induced nonautoimmune Hemolytic disease of the newborn Aplastic (mostly normo-) Hereditary: Fanconi anemia Diamond–Blackfan anemia Acquired: PRCA Sideroblastic anemia Myelophthisic Blood tests MCV Normocytic Microcytic Macrocytic MCHC Normochromic Hypochromic Other Methemoglobinemia Sulfhemoglobinemia Reticulocytopenia Coagulation/ coagulopathy ↑ Hyper- coagulability primary: Antithrombin III deficiency Protein C deficiency/Activated protein C resistance/Protein S deficiency/Factor V Leiden Prothrombin G20210A Sticky platelet syndrome acquired:Thrombocytosis essential DIC Congenital afibrinogenemia Purpura fulminans autoimmune Antiphospholipid ↓ Hypo- coagulability Thrombocytopenia Thrombocytopenic purpura: ITP Evans syndrome TM TTP Upshaw Schulman syndrome Heparin-induced thrombocytopenia May–Hegglin anomaly Platelet function adhesion Bernard–Soulier syndrome aggregation Glanzmann's thrombasthenia platelet storage pool deficiency Hermansky–Pudlak syndrome Gray platelet syndrome Clotting factor Hemophilia A/VIII B/IX C/XI von Willebrand disease Hypoprothrombinemia/II XIII Dysfibrinogenemia Index of cells from bone marrow Description Immune system Cells Physiology coagulation proteins granule contents colony-stimulating heme and porphyrin metabolism intermediates Disease Red blood cell Monocyte and granulocyte Neoplasms and cancer Histiocytosis Symptoms and signs eponymous Blood tests findings Treatment Transfusion Drugs thrombosis bleeding other

Myeloid hematological malignancy/leukemia histology (ICD-O 9590–9989, C81–C96, 200–208) CFU-GM/ and other granulocytes CFU-GM Myelocyte AML: Acute myeloblastic leukemia M0 M1 M2 APL/M3 MP Chronic neutrophilic leukemia Monocyte AML AMoL/M5 Myeloid dendritic cell leukemia CML Philadelphia chromosome Accelerated phase chronic myelogenous leukemia Myelomonocyte AML M4 MD-MP Juvenile myelomonocytic leukemia Chronic myelomonocytic leukemia Other Histiocytosis CFU-Baso AML Acute basophilic CFU-Eos AML Acute eosinophilic MP Chronic eosinophilic leukemia/Hypereosinophilic syndrome MEP CFU-Meg AML AMKL/M7 MP Essential thrombocytosis CFU-E AML Erythroleukemia/M6 MP Polycythemia vera MD Refractory anemia Refractory anemia with excess of blasts Chromosome 5q deletion syndrome Sideroblastic anemia Paroxysmal nocturnal hemoglobinuria Refractory cytopenia with multilineage dysplasia CFU-Mast Mastocytoma Mast cell leukemia Mast cell sarcoma Systemic mastocytosis Mastocytosis: Diffuse cutaneous mastocytosis Erythrodermic mastocytosis Adult type of generalized eruption of cutaneous mastocytosis Urticaria pigmentosa Mast cell sarcoma Solitary mastocytoma Systemic mastocytosis Xanthelasmoidal mastocytosis Multiple/unknown AML Acute panmyelosis with myelofibrosis Myeloid sarcoma MP Myelofibrosis Acute biphenotypic leukaemia Index of cells from bone marrow Description Immune system Cells Physiology coagulation proteins granule contents colony-stimulating heme and porphyrin metabolism intermediates Disease Red blood cell Monocyte and granulocyte Neoplasms and cancer Histiocytosis Symptoms and signs eponymous Blood tests findings Treatment Transfusion Drugs thrombosis bleeding other

Sex linkage: X-linked disorders X-linked recessive Immune Chronic granulomatous disease (CYBB) Wiskott–Aldrich syndrome X-linked severe combined immunodeficiency X-linked agammaglobulinemia Hyper-IgM syndrome type 1 IPEX X-linked lymphoproliferative disease Properdin deficiency Hematologic Haemophilia A Haemophilia B X-linked sideroblastic anemia Endocrine Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy KAL1 Kallmann syndrome X-linked adrenal hypoplasia congenita Metabolic Amino acid: Ornithine transcarbamylase deficiency Oculocerebrorenal syndrome Dyslipidemia: Adrenoleukodystrophy Carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency Pyruvate dehydrogenase deficiency Danon disease/glycogen storage disease Type IIb Lipid storage disorder: Fabry's disease Mucopolysaccharidosis: Hunter syndrome Purine-pyrimidine metabolism: Lesch–Nyhan syndrome Mineral: Menkes disease/Occipital horn syndrome Nervous system X-linked mental retardation: Coffin–Lowry syndrome MASA syndrome X-linked alpha thalassemia mental retardation syndrome Siderius X-linked mental retardation syndrome Eye disorders: Color blindness (red and green, but not blue) Ocular albinism (1) Norrie disease Choroideremia Other: Charcot–Marie–Tooth disease (CMTX2-3) Pelizaeus–Merzbacher disease SMAX2 Skin and related tissue Dyskeratosis congenita Hypohidrotic ectodermal dysplasia (EDA) X-linked ichthyosis X-linked endothelial corneal dystrophy Neuromuscular Becker's muscular dystrophy/Duchenne Centronuclear myopathy (MTM1) Conradi–Hünermann syndrome Emery–Dreifuss muscular dystrophy 1 Urologic Alport syndrome Dent's disease X-linked nephrogenic diabetes insipidus Bone/tooth AMELX Amelogenesis imperfecta No primary system Barth syndrome McLeod syndrome Smith–Fineman–Myers syndrome Simpson–Golabi–Behmel syndrome Mohr–Tranebjærg syndrome Nasodigitoacoustic syndrome X-linked dominant X-linked hypophosphatemia Focal dermal hypoplasia Fragile X syndrome Aicardi syndrome Incontinentia pigmenti Rett syndrome CHILD syndrome Lujan–Fryns syndrome Orofaciodigital syndrome 1 Craniofrontonasal dysplasia

Genetic disorder, membrane: ABC-transporter disorders ABCA ABCA1 (Tangier disease) ABCA3 (Surfactant metabolism dysfunction 3) ABCA4 (Stargardt disease 1, Retinitis pigmentosa 19) ABCA12 (Harlequin-type ichthyosis, Lamellar ichthyosis 2) ABCB ABCB4 (Progressive familial intrahepatic cholestasis 3) ABCB7 (ASAT) ABCB11 (Progressive familial intrahepatic cholestasis 2) ABCC ABCC2 (Dubin–Johnson syndrome) ABCC6 (Pseudoxanthoma elasticum) ABCC7 (Cystic fibrosis) ABCC8 (HHF1, TNDM2) ABCC9 (Dilated cardiomyopathy 1O) ABCD ABCD1 (Adrenoleukodystrophy, Adrenomyeloneuropathy) ABCG ABCG5 (Sitosterolemia) ABCG8 (Gallbladder disease 4, Sitosterolemia) see also ABC transporters Index of cells Description Structure nucleus chromosome genetics Organelles peroxisome cytoskeleton centrosome epithelia cilia mitochondria Membranes proteins cell adhesions Membrane transport ion channels vesicular transport solute carrier ABC transporters ATPase oxidoreduction-driven Disease Structural peroxisome cytoskeleton cilia mitochondria nucleus scleroprotein Membrane channelopathy solute carrier ATPase ABC transporters other extracellular ligands cell surface receptors intracellular signalling Vesicular transport Pore-forming toxins