Sideroblastic anemia, or sideroachrestic anemia, is a form of
anemia
Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...
in which the
bone marrow
Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
produces ringed sideroblasts rather than healthy
red blood cell
Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...
s (erythrocytes).
In sideroblastic anemia, the body has iron available but cannot incorporate it into
hemoglobin
Hemoglobin (haemoglobin, Hb or Hgb) is a protein containing iron that facilitates the transportation of oxygen in red blood cells. Almost all vertebrates contain hemoglobin, with the sole exception of the fish family Channichthyidae. Hemoglobin ...
, 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 chromosome abnormality. Although polygenic disorders ...
or indirectly as part of
myelodysplastic syndrome,
which can develop into
hematological malignancies (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 haematopoiesis, normal blood cell production. Sympt ...
).
Sideroblasts (''
sidero-'' + ''
-blast'') are
nucleated erythroblast
A nucleated red blood cell (NRBC), also known by #Nomenclature, 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 mamm ...
s (precursors to mature red blood cells) with granules of iron accumulated in the
mitochondria
A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
surrounding the
nucleus. 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 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 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 (, from Ancient Greek '' σπλήν'', splḗn) is an organ (biology), organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter.
The spleen plays important roles in reg ...
and
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
. Heart disease, liver damage, and
kidney failure
Kidney failure, also known as renal failure or end-stage renal disease (ESRD), 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 fa ...
can result from iron buildup in these organs.
Symptoms of sideroblastic anemia usually resemble the common symptoms of anemia. In addition to the symptoms listed above, patients with sideroblastic anemia may experience shortness of breath, heart palpitations, and headache. Some patients may have bronze-colored skin due to an overload of iron. Patients with syndromic hereditary sideroblastic anemia may experience diabetes mellitus and deafness.
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 (American English), or haem (Commonwealth English, both pronounced /Help:IPA/English, hi:m/ ), is a ring-shaped iron-containing molecule that commonly serves as a Ligand (biochemistry), ligand of various proteins, more notably as a Prostheti ...
synthesis or processing. This leads to granular deposition of iron in the
mitochondria
A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
that form a ring around the
nucleus of the developing
red blood cell
Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...
. 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,
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 (lyonizations).
** 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
Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...
,
myopathy
In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. ''Myopathy'' means muscle disease ( Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meaning implies that the primary defec ...
, 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 (vitamin B
6 is the cofactor in the first step of heme synthesis),
lead poisoning
Lead poisoning, also known as plumbism and saturnism, is a type of metal poisoning caused by lead in the body. Symptoms may include abdominal pain, constipation, headaches, irritability, memory problems, infertility, numbness and paresthesia, t ...
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 (which interferes with pyridoxine metabolism),
chloramphenicol (which, by inhibiting the synthesis of mitochondrial membrane protein, impairs mitochondrial respiration
),
cycloserine, and
linezolid.
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 is commonly decreased (i.e., a
microcytic anemia), but it may also be normal or even high. The
RDW is increased with the
red blood cell
Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...
histogram shifted to the left.
Leukocyte
White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
s and
platelet
Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...
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 and freely circulate in the blood. Clinicians order this laboratory test when they are concerned about iron deficiency, which can ca ...
, percentage saturation and
ferritin
Ferritin is a universal intracellular and extracellular 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. ...
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 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
ferritin
Ferritin is a universal intracellular and extracellular 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. ...
levels
* decreased
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 ...
* 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 t ...
*
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
Lead poisoning, also known as plumbism and saturnism, is a type of metal poisoning caused by lead in the body. Symptoms may include abdominal pain, constipation, headaches, irritability, memory problems, infertility, numbness and paresthesia, t ...
, 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, Parisian and Paris blue) is a dark blue pigment produced by oxidation of ferrous ferrocyanide salts. It has the chemical formula . It consists of cations, where iron is in the oxidat ...
stain of RBC in marrow shows ringed sideroblasts. Prussian blue staining involves a non-enzymatic reaction of ferrous iron with
ferrocyanide
Ferrocyanide is the anion 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(CN)6sup>4− is ...
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
Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production ( erythropoiesis) in th ...
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 B
6). 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 B
6 is sufficient to correct the anemia.
Deferoxamine, a
chelating agent, 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 B
6.
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
Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...
*
Siderosis
*
List of hematologic conditions
*
Hematopoietic stem cell transplantation
References
External links
GeneReviews/NCBI/NIH/UW entry on X-Linked Sideroblastic Anemia and Ataxia
{{ABC transporter disorders
Myeloid neoplasia
Aplastic anemias