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SIDEROBLASTIC ANEMIAS

DR DA SILVA MARQUES

DEFINITION
Sideroblastic anemias are a

heterogeneous group of disorders


characterized by anemia of varying
severity and diagnosed by finding ring
sideroblasts in the bone marrow
aspirate
Defects involving incorporation of iron
into the heme molecule result in
sideroblastic anemias

Pathophysiology

Sideroblasts are not pathognomonic of any one

disease but rather are a bone marrow manifestation


of several diverse disorders. On a marrow stained
with Prussian blue, a sideroblast is an erythroblast
that has stainable deposits of iron in cytoplasm.
When abundant, these deposits form a ring around
the nucleus, and the cells become ring sideroblasts

Pathophysiology

Under normal

circumstances, this iron


would have been used to
make heme. The process
only occurs in the bone
marrow, because mature
erythrocytes lack
mitochondria, the nexus
of heme synthesis

In the pyridoxine-

responsive
subtype, point
mutations on the
X chromosome
have been
identified that
result in a -amino
levulinic acid
synthase (ALAS-2)
with very low
enzymatic activity

CLASSIFICATION
Congenital sideroblastic anemias
These disorders are genetically and clinically

heterogeneous with diverse underlying causes,


inheritance patterns, clinical phenotypes, and
associated features.
Most appear as isolated anemia while uncommonly
the defect also affects other systems ( syndromic
sideroblastic anemias).

CLASSIFICATION
Acquired clonal sideroblastic anemia
This disorder is included as a subtype(s) of the

myelodysplastic syndromes (MDS), where it is


designated as refractory anemia with ringed
sideroblasts (RARS). It also occurs as two variants
when associated with thrombocytosis (RARS-T) or
with other cytopenias (RCMD-RS).
The fundamental cause of these syndromes is
undefined.

CLASSIFICATION
Acquired metabolic sideroblastic anemia Diverse

factors that include alcohol, certain drugs (eg,


isoniazid chloramphenicol ), copper deficiency
(zinc toxicity), and hypothermia can lead to a
sideroblastic anemia.
This condition is fully reversible when the
offending factor is removed.

Clinical
Typically the anemia of X-linked sideroblastic anemia

manifests in infancy or childhood, but the milder forms


of anemia may not be found until midlife. Even elderly
patients have been diagnosed with this anemia.150 Some
cases may be discovered only during family surveys,
which should always be undertaken when hereditary
sideroblastic anemia is diagnosed. Still other patients
may present with features of iron overload, such as
diabetes or cardiac failure. Iron overload occurs
commonly even with mild anemia and may occasionally
be seen with female carriers. Enlargement of the liver
and spleen may occur with mild abnormalities of liver
function tests.

X-linked sideroblastic anemia


Apart from symptoms and signs of anemia, all patients

exhibit manifestations of iron overload, due to the


increased absorption of iron owing to the presence of
ineffective erythropoiesis
This is invariably accentuated in transfusion-dependent
individuals.
Clinical diabetes mellitus or abnormal glucose tolerance
may be related to the degree of iron overload. The most
dangerous complications of the iron overload are cardiac
arrhythmias and heart failure, which usually occur late
in the course of the disease

X-linked sideroblastic anemia


Mild to moderate degrees of

hepatosplenomegaly are common, but liver


function is usually normal or only mildly
disturbed at presentation. Liver biopsy
reveals a pattern of iron deposition that is
indistinguishable from that of hereditary
hemochromatosis

DIAGNOSIS
Microcytic, normocytic, or macrocytic

anemia
The presence of ring sideroblasts on
bone marrow examination
Commonly, evidence for systemic iron
overload unless iron deficiency is also
present (eg, from excessive menstrual
blood loss

FBC
A common but not constant finding in the sideroblastic

anemias is the presence of erythrocyte microcytosis (low


mean corpuscular volume, MCV), and hypochromia (low
mean corpuscular hemoglobin, MCH), the degree of which
roughly parallels the severity of the anemia
Typical variation in RBC size and shape is reflected in an
abnormally wide red cell volume distribution width (RDW)
. Siderocytes, hypochromic red cells with coarse basophilic
granules that stain positive for iron (ie, Pappenheimer
bodies) representing mature, enucleated erythrocyte
counterparts of the ring sideroblasts may be seen in the
peripheral blood in those with more severe degrees of
anemia picture 4 ) and are always numerous if
splenectomy has been performed.

Pappenheimer bodies (Prussian blue stain).

BM

Iron Study/Iron overload


Serum iron concentration is increased,

serum ferritin >500 mcg/L), best


documented by liver biopsy or T2* by
MRI
Transferrin shows an increased
percentage of saturation with iron.
Serum ferritin levels are invariably
increased

Ineffective erythropoiesis
mild increase in bilirubin

concentration,
decrease in haptoglobin levels
mild increase in lactate dehydrogenase
levels
and normal or slight increase in
reticulocyte numbers.
ferrokinetic measurements

Therapy for Hereditary Sideroblastic Anemia


A trial of pyridoxine (100 to 200 mg/day taken orally) is

indicated for 3 months for all patients with hereditary


sideroblastic anemia
About 25% to 50% of patients with hereditary
sideroblastic anemia show a full or partial response to
pyridoxine, and this vitamin should be continued on a
lifelong basis in the responders.
lower maintenance dose reduction, because long-term
therapy with pyridoxine at 100 to 200 mg/day has been
associated with peripheral neuropathy.154 The adult
nutritional requirement for pyridoxine is 1 to 2 mg/day;
some patients have been maintained on as little as 4
mg/day as a supplement.
Folic acid supplements should also be administered
because the erythroid hyperplasia increases demand for
this vitamin.

Therapy for Hereditary Sideroblastic Anemia


Transfusions are the mainstay of treatment for

severe anemia unresponsive to pyridoxine. Regular


administration of packed red cells using white blood
cell filters are given to relieve symptoms and permit
normal childhood development.
Iron overload and secondary hemosiderosis rapidly
progress after transfusions
chelation therapy with desferrioxamine or oral
deferasirox In patients who have more severe
anemia, and in those who require regular red cell
transfusions and thus cannot undergo phlebotomy,
chelation of the excess iron is undertaken with an
iron chelating agent

Therapy for Hereditary Sideroblastic Anemia


Iron removal may be of great benefit for patients who

have mild or moderate anemia and evidence of iron


overload.151,152 These patients can often tolerate
intermittent phlebotomy, which is preferable to chelation
therapy for iron removal, and should be continued to
reduce ferritin levels to less than 300 ng/mL.

All patients with iron overload should avoid ingestion of

ascorbic acid supplements, which enhance iron


absorption and increase the tissue toxicity of elemental
iron. Alcohol should also be avoided. Splenectomy is
contraindicated in this disease.

Therapy for Hereditary Sideroblastic Anemia


Therapeutic phlebotomy . Graded phlebotomies can be

performed in patients who have responded to pyridoxine


supplements, and in all others with mild or moderate
anemia (ie, hemoglobin >9 g/dL) when there are no
contraindications to therapeutic phlebotomy, such as
congestive failure .
Once the serum ferritin level has been reduced sufficiently,
maintenance phlebotomies are continued on a regular
basis for life, in order to prevent reaccumulation of iron

Splenectomy---NOoooo
There has been a temptation to perform

splenectomy in patients with severe anemia


and a significant degree of splenomegaly
with suspected splenic sequestration of red
cells. However, this procedure is invariably
complicated by postoperative
thromboembolic events and often a fatal
outcome . Factors other than persistent
thrombocytosis appear to play a role; control
of the platelet count and anticoagulant
therapy are not usually effective.

For these reasons, splenectomy is

contraindicated