Sideroblastic anemia, or sideroachrestic anemia, is a form of

anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...

in which the bone marrow produces ringed sideroblasts rather than healthy

red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...

s (erythrocytes). In sideroblastic anemia, the body has iron available but cannot incorporate it into

hemoglobin Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyt ...

, which red blood cells need in order to transport oxygen efficiently. The disorder may be caused either by a

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

or indirectly as part of

myelodysplastic syndrome A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may ...

, which can develop into

hematological malignancies Tumors of the hematopoietic and lymphoid tissues (American English) or tumours of the haematopoietic and lymphoid tissues (British English) are tumors that affect the blood, bone marrow, lymph, and lymphatic system. Because these tissues are al ...

(especially

acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may inclu ...

). Sideroblasts ('' sidero-'' + '' -blast'') are

nucleated The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, ...

erythroblast A nucleated red blood cell (NRBC), also known by several other names, is a red blood cell that contains a cell nucleus. Almost all vertebrate organisms have hemoglobin-containing cells in their blood, and with the exception of mammals, all of t ...

s (precursors to mature red blood cells) with granules of iron accumulated in the mitochondria surrounding the

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom * Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucl ...

. Normally, sideroblasts are present in the bone marrow, and enter the circulation after maturing into a normal erythrocyte. The presence of sideroblasts ''per se'' does not define sideroblastic anemia. Only the finding of ring (or ringed) sideroblasts characterizes sideroblastic anemia. Ring sideroblasts are named so because iron-laden mitochondria form a ring around the nucleus. It is a subtype of

basophilic Basophilic is a technical term used by pathologists. It describes the appearance of cells, tissues and cellular structures as seen through the microscope after a histological section has been stained with a basic dye. The most common such dye i ...

granules of the erythrocyte, but which can only be seen in bone marrow. To count a cell as a ring sideroblast, the ring must encircle a third or more of the nucleus and contain five or more iron granules, according to the 2008

WHO Who or WHO may refer to: * Who (pronoun), an interrogative or relative pronoun * Who?, one of the Five Ws in journalism * World Health Organization Arts and entertainment Fictional characters * Who, a creature in the Dr. Seuss book '' Horton He ...

classification of the tumors of the hematopoietic and lymphoid tissues.

Types

The WHO International Working Group on Morphology of MDS (IWGM-MDS) defined three types of sideroblasts: # Type 1 sideroblasts: fewer than 5 siderotic granules in the cytoplasm # Type 2 sideroblasts: 5 or more siderotic granules, but not in a perinuclear distribution # 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. Type 1 and type 2 are found in non-sideroblastic anemias. Type 3 is found only in sideroblastic anemia.

Symptoms and signs

Symptoms of sideroblastic anemia include skin paleness, fatigue, dizziness, and enlarged

spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .

and

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

. Heart disease, liver damage, and

kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

can result from iron buildup in these organs.

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 Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consis ...

synthesis or processing. This leads to granular deposition of iron in the mitochondria that form a ring around the

of the developing

. 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 Delta-aminolevulinate synthase 2 also known as ALAS2 is a protein that in humans is encoded by the ''ALAS2'' gene. ALAS2 is an aminolevulinic acid synthase. The product of this gene specifies an erythroid-specific mitochondrially located enzym ...

, 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 X-inactivation (also called Lyonization, after English geneticist Mary Lyon) is a process by which one of the copies of the X chromosome is inactivated in therian female mammals. The inactive X chromosome is silenced by being packaged into a ...

(lyonizations). ** Autosomal recessive sideroblastic anemia involves mutations in the

SLC25A38 Mitochondrial glycine transporter is a protein that in humans is encoded by the ''SLC25A38'' gene. SLC25A38 is involved in mitochondrial handling of glycine and is needed for the first step in heme synthesis. Mutations in this gene can lead to an ...

gene. The function of this protein is not fully understood, but it is involved in mitochondrial transport of glycine. Glycine is a substrate for

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 Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

, myopathy, and

pancreatic insufficiency Exocrine pancreatic insufficiency (EPI) is the inability to properly digest food due to a lack of digestive enzymes made by the pancreas. EPI is found in humans afflicted with cystic fibrosis and Shwachman–Diamond syndrome, and is common in ...

. * Acquired clonal sideroblastic anemia ** Clonal sideroblastic anemias fall under the broader category of

myelodysplastic syndromes A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may ...

(MDS). Three forms exist and include refractory anemia with ringed sideroblasts (RARS), refractory anemia with ringed sideroblasts and

thrombocytosis Thrombocythemia is a condition of high platelet (thrombocyte) count in the blood. Normal count is in the range of 150x109 to 450x109 platelets per liter of blood, but investigation is typically only considered if the upper limit exceeds 750x109/L. ...

(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 Vitamin B6 is one of the B vitamins, and thus an essential nutrient. The term refers to a group of six chemically similar compounds, i.e., "vitamers", which can be interconverted in biological systems. Its active form, pyridoxal 5′-phospha ...

(vitamin B₆ is the cofactor in the first step of heme synthesis), lead poisoning and

copper deficiency Copper deficiency, or hypocupremia, is defined either as insufficient copper to meet the needs of the body, or as a serum copper level below the normal range. Symptoms may include fatigue, decreased red blood cells, early greying of the hair, an ...

. Excess zinc can indirectly cause sideroblastic anemia by decreasing absorption and increasing excretion of copper. Antimicrobials that may lead to sideroblastic anemia include

isoniazid Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic used for the treatment of tuberculosis. For active tuberculosis it is often used together with rifampicin, pyrazinamide, and either streptomycin or ethambutol. For la ...

(which interferes with pyridoxine metabolism), chloramphenicol (which, by inhibiting the synthesis of mitochondrial membrane protein, impairs mitochondrial respiration),

cycloserine Cycloserine, sold under the brand name Seromycin, is a GABA transaminase inhibitor and an antibiotic, used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active drug resistant tuberculosis. It ...

, and

linezolid Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, v ...

Diagnosis

Ringed sideroblasts are seen in the bone marrow. On the peripheral blood smear can be found erythrocytes with basophilic stippling (cytoplasmic granules of RNA precipitates) and Pappenheimer bodies (cytoplasmic granules of iron). The anemia is moderate to severe and dimorphic. Microscopic viewing of the red blood cells will reveal marked unequal cell size and abnormal cell shape. Basophilic stippling is marked and target cells are common. The

mean cell volume The mean corpuscular volume, or mean cell volume (MCV), is a measure of the average volume of a red blood corpuscle (or red blood cell). The measure is obtained by multiplying a volume of blood by the proportion of blood that is cellular (the hema ...

is commonly decreased (i.e., a

microcytic anemia Microcytic anaemia is any of several types of anemia characterized by smaller than normal red blood cells (called microcytes). The normal mean corpuscular volume (abbreviated to MCV on full blood count results, and also known as mean cell volume) ...

), but it may also be normal or even high. The RDW is increased with the

histogram shifted to the left. Leukocytes and

platelet Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby i ...

s are normal. Bone marrow shows erythroid hyperplasia with a maturation arrest.In excess of 40% of the developing erythrocytes are ringed sideroblasts.

Serum iron Serum iron is a medical laboratory test that measures the amount of circulating iron that is bound to transferrin (90%) and serum ferritin (10%). Clinicians order this laboratory test when they are concerned about iron deficiency, which can cause ...

, percentage saturation and

ferritin Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. It is the primary ' ...

are increased. The

total iron-binding capacity Total iron-binding capacity (TIBC) or sometimes transferrin iron-binding capacity is a medical laboratory test that measures the blood's capacity to bind iron with transferrin. Transferrin can bind two atoms of ferric iron (Fe3+) with high affinit ...

of the cells is normal to decreased. Stainable marrow hemosiderin is increased.

Classification

Sideroblastic anemia is typically divided into subtypes based on its cause. * Hereditary or congenital sideroblastic anemia may be X-linked or autosomal.

GLRX5 Glutaredoxin 5, also known as GLRX5, is a protein which in humans is encoded by the ''GLRX5'' gene located on chromosome 14. This gene encodes a mitochondrial protein, which is evolutionarily conserved. It is involved in the biogenesis of iro ...

has also been implicated. * Acquired, or secondary, sideroblastic anemia develops after birth and is divided according to its cause.

Laboratory findings

* Serum Iron: high * increased

levels * decreased

* high

transferrin saturation Transferrin saturation (TS), measured as a percentage, is a medical laboratory value. It is the value of serum iron divided by the total iron-binding capacity of the available transferrin, the main protein that binds iron in the blood, this value ...

Hematocrit The hematocrit () (Ht or HCT), also known by several other names, is the volume percentage (vol%) of red blood cells (RBCs) in blood, measured as part of a blood test. The measurement depends on the number and size of red blood cells. It is norm ...

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 Prussian blue (also known as Berlin blue, Brandenburg blue or, in painting, Parisian or Paris blue) is a dark blue pigment produced by oxidation of ferrous ferrocyanide salts. It has the chemical formula Fe CN)">Cyanide.html" ;"title="e(Cyani ...

stain of RBC in marrow shows ringed sideroblasts. Prussian blue staining involves a non-enzymatic reaction of ferrous iron with

ferrocyanide Ferrocyanide is the name of the anion CN)6">cyanide.html" ;"title="e(cyanide">CN)6sup>4−. Salts of this coordination complex give yellow solutions. It is usually available as the salt potassium ferrocyanide, which has the formula K4Fe(CN)6. e ...

forming ferric-ferrocyanide, which is blue in color. A

counterstain A counterstain is a stain with colour contrasting to the principal stain, making the stained structure easily visible using a microscope. Examples include the malachite green counterstain to the fuchsine stain in the Gimenez staining technique ...

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. Some cases have been reported that the anemia is reversed or heme level is improved through use of moderate to high doses of pyridoxine (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

-induced sideroblastic anemia, the addition of B₆ is sufficient to correct the anemia.

Deferoxamine Deferoxamine (DFOA), also known as desferrioxamine and sold under the brand name Desferal, is a medication that binds iron and aluminium. It is specifically used in iron overdose, hemochromatosis either due to multiple blood transfusions or an un ...

, a

chelating agent Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central metal atom. These ligands ar ...

, is used to treat iron overload from transfusions. Therapeutic phlebotomy can be used to manage iron overload.Peto, T. E. A., Pippard, M. J., Weatherall, D. J. Iron overload in mild sideroblastic anaemias" ''Lancet'' 321: 375-378, 1983. Note: Originally Volume I.

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.

References

External links

GeneReviews/NCBI/NIH/UW entry on X-Linked Sideroblastic Anemia and Ataxia
{{ABC transporter disorders Myeloid neoplasia Genetic disorders by system Aplastic anemias