SIDEROBLASTIC ANEMIA

REVIEW ARTICLE
BY
ISLAM AHMADY MOHAMMED ISMAIL
Student in the first year Faculty of Medicine- Zagazig University
No: 1734

Group : (6)

UNDER SUPERVISION OF

PROFESSOR DR/ SHERIF WAGIEH

PHYSIOLOGY DEPARTMENT

ZAGAZIG UNIVERSITY

2014

SIDEROBLASTIC ANEMIA
INTRODUCTION
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

[2]
indirectly
as
part
of myelodysplastic
syndrome
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 are atypical, abnormal nucleated erythroblasts (precursors to mature red blood cells) with granules of
iron accumulated in perinucle mitochondria.[3] . Sideroblasts are seen in aspirates of bone marrow.
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.

DEFINITION
Sideroblastic anemias, a group of heterogenous disorders, produce a common defectfailure to use iron in
hemoglobin (Hb) synthesis, despite the availability of adequate iron stores. This is a refractory anaemia with
hypochromic cells in the peripheral blood and increased marrow iron; It is defined by the presence of many
pathological ring sideroblasts in the bone marrow [5]

PATHOPHYSIOLOGY:
Adult human bone marrow synthesizes 41014 molecules of hemoglobin every second. Heme and globin chains
(alpha and beta) in adults are manufactured in separate cell compartments, mitochondria and cytoplasm, respectively,
and then combined in cytoplasm in an amazingly accurate manner.
Four major problems can manifest during this delicate process:

 Qualitative defects of globin chain synthesis result in hemoglobinopathies such as sickle cell disease.
Quantitative defects of globin chain synthesis result in hemoglobinopathies such as thalassemia.
Defects in synthesis of the heme portion result in porphyrias.
Defects involving incorporation of iron into the heme molecule result in sideroblastic anemias.

OVERVIEW OF IRON AND HEME

OVERVIEW OF HEME SYNTHESIS

CAUSES OF SIDEROBLASTIC ANEMIA

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,[6] 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, andpancreatic 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.[7]

SYMPTOMS
Nonspecific clinical effects, which may exist for several years before being identified. Such effects include:
anorexia,
fatigue,
weakness,
dizziness,
pale skin and mucous membranes
enlarged lymph nodes.

 Heart and liver failure may develop from excessive iron accumulation in these organs, causing dyspnea,
exertional angina, slight jaundice, and hepatosplenomegaly.
Hereditary sideroblastic anemia is associated with increased GI absorption of iron, causing signs of
hemosiderosis. Additional symptoms in secondary sideroblastic anemia depend on the underlying cause.

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.[8]

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 withferrocyanide forming ferric-ferrocyanide, which is blue in
color. A counterstain may be used to provide better visualization [9].

TREATMENT
The underlying cause determines the type of treatment.
Hereditary form
Hereditary sideroblastic anemia usually responds to several weeks of treatment with high doses of pyridoxine
(vitamin B6).
Primary acquired form
5

 Elderly patients with sideroblastic anemiamost commonly the primary acquired formare less likely to
improve quickly and are more likely to develop serious complications. Deferoxamine may be used to treat
chronic iron overload in selected patients.
Carefully cross-matched transfusions (providing needed Hb) or high doses of androgens are effective
palliative measures for some patients with the primary acquired form of sideroblastic anemia. However, this
form is essentially refractory to treatment and usually leads to death from acute leukemia or from
respiratory or cardiac complications.
Secondary acquired form
The secondary acquired form generally subsides after the causative drug or toxin is removed or the
underlying condition is adequately treated. Folic acid supplements may also be beneficial when concomitant
megaloblastic nuclear changes in RBC precursors are present.
Bone marrow transplant (BMT) can be considered in severe cases.[9]

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 [10].

REFERENCES:
1- Fleming MD. Congenital sideroblastic anemias: iron and heme lost in mitochondrial translation. Hematology Am Soc
Hematol Educ Program 2011; 2011:525.
2-Bottomley SS. Sideroblastic anemias. In: Wintrobe's Clinical Hematology, 13th ed, Greer JP, Arber DA, Glader B, et al.
(Eds), Lippincott, Williams and Wilkins, Philadelphia 2014. p.643.
3-Ben Salem D, Cercueil JP, Ricolfi F, Kraus D. Case 75: erythropoietic hemochromatosis. Radiology 2004; 233:116.
4- Camaschella C (September 2008). "Recent advances in the understanding of inherited sideroblastic anaemia". Br. J.
Haematol. 143 (1): 2738.
5- Papadakis, Maxine A.; Tierney, Lawrence M.; McPhee, Stephen J. (2005). "Sideroblastic Anemia". Current Medical
Diagnosis & Treatment, 2006.
6- Bottomley SS. Sideroblastic anaemia. Clin Haematol 1982; 11:389
7- Saini, N; Jacobson, JO; Jha, S; Saini, V; Weinger, R (April 2012). "The perils of not digging deep enough--uncovering a
rare cause of acquired anemia.". American journal of hematology 87 (4): 4136. doi:10.1002/ajh.22235. PMID 22120958
6

8- Bottomley SS. The spectrum and role of iron overload in sideroblastic anemia. Ann N Y Acad Sci 1988; 526:331.
9- Vial T, Grignon M, Daumont M, et al. Sideroblastic anaemia during fusidic acid treatment. Eur J Haematol 2004; 72:358.

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