Clinical aspects, diagnosis, and treatment of the sideroblastic anemias

Author
Sylvia S Bottomley, MD
Section Editor
Stanley L Schrier, MD
Deputy Editor
Stephen A Landaw, MD, PhD
Last literature review version 18.3: septiembre 2010 | This topic last updated:
julio 28, 2010 (More)
INTRODUCTION — The principal clinical features of all sideroblastic anemias (table 1)
are those of a variably severe although indolent or progressive anemia. However, mild
life-long anemia may go unnoticed, and symptoms and signs of the iron overload
associated with most irreversible forms of sideroblastic anemia may lead to discovery
of the underlying disorder. The history and clinical findings, together with typical
laboratory features, usually permit accurate diagnosis of each category of sideroblastic
anemia. The molecular defects can be identified in several congenital forms and
suggested in some patients with clonal sideroblastic anemia. (See "Causes of
congenital and acquired sideroblastic anemias".)

The clinical aspects, diagnosis, and treatment of the sideroblastic anemias will be
discussed here [1]. The pathophysiology of these disorders is discussed separately.
(See "Pathophysiology of the sideroblastic anemias".)

CONGENITAL SIDEROBLASTIC ANEMIAS — In the non-syndromic congenital forms

the anemia generally remains stable over many years. However, in some individuals
there is an unexplained progression of the anemia over time. Although unrelated
causes need to be ruled out (eg, folate deficiency, systemic disease), this may be
attributable in part to:

 Prior intake of pyridoxine as part of a multivitamin preparation (which has

recently been discontinued), changes in dietary habits, or alterations in
pyridoxine metabolism with age in patients with pyridoxine-responsive X-
linked sideroblastic anemia.
 Skewing of X inactivation patterns (lyonization) in hematopoietic cells with age
in women with X-linked sideroblastic anemia. In such cases, the normal allele
becomes progressively inactivated, leading to a greater relative expression of
the mutant allele [2,3].
 “Toxic” effects of the associated iron overload or accompanying hypersplenism.
(See "Pathophysiology of the sideroblastic anemias", section on 'Iron
overload'.)
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
(picture 1). Not infrequently, well-established but asymptomatic micronodular cirrhosis
is discovered by the third or fourth decade, which does not correlate with severity of
the anemia [4,5] (picture 2).

Apart from symptoms and signs of anemia, all patients without an associated genetic
syndrome (with the exception of protoporphyria) eventually exhibit manifestations of
iron overload, due to the increased absorption of iron associated with the presence of
ineffective erythropoiesis [6]. Clinical diabetes or abnormal glucose tolerance may or
may not 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 (picture 3). In severely affected children, growth and
development may also be impaired.

Diagnosis — A constellation of laboratory findings represents the diagnostic features

of these disorders:

Complete blood count — The hemoglobin level is highly variable among patients, but
is usually below 7 g/dL at the time of diagnosis in the autosomal recessive sideroblastic
anemia due to SLC25A38 defects. Leukocyte and platelet values are generally normal,
but may be reduced in the presence of splenomegaly (hypersplenism). (See "Extrinsic
nonimmune hemolytic anemia due to mechanical damage: Fragmentation hemolysis
and hypersplenism", section on 'Extravascular nonimmune hemolysis due to
hypersplenism'.)

A nearly constant finding 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 (picture 4).
Typical variation in RBC size and shape is reflected in an abnormally wide red cell
volume distribution width (RDW) (figure 1). Occasional siderocytes are seen in more
anemic patients and are numerous if splenectomy has been performed.

In females with the X-linked disorder, the MCV is often normal or increased, and a
biphasic automated red cell volume histogram is typically present if the anemia is not
severe (figure 1), reflecting the presence of a double population of red cells.

Iron studies — Along with an increased serum transferrin saturation, reduced

transferrin, and increased serum ferritin levels, marrow reticuloendothelial iron is
strikingly increased.
Magnetic resonance imaging shows distinctive features of the iron overload. The low
signal intensity on T1- and T2-weighted images, caused by the paramagnetic effect of
intracellular iron, is seen in the liver and bone marrow, but not in the spleen in
untransfused patients, and is characteristic of the erythropoietic hemochromatosis [7].

The degree of iron overload is best assessed by obtaining a liver biopsy, as serum
ferritin values afford only a rough indication of the degree of iron overload. The liver
biopsy also provides additional prognostic information through demonstration of the
degree of liver damage and/or cirrhosis. (See "Pathophysiology and diagnosis of iron
overload syndromes" and "Hepatic iron concentration and hepatic iron index in the
diagnosis of iron overload and hereditary hemochromatosis".)

In the exceptional case with concomitant iron deficiency, most commonly encountered
in young females with excess menstrual blood losses, the ring sideroblast abnormality
may be masked, such that only occasional ring sideroblasts may be found [8]. In these
patients, iron studies show a reduced or normal serum iron, along with a low ferritin
concentration, consistent with the presence of an unrelated iron deficiency state.

Erythrocyte protoporphyrin — In X-linked sideroblastic anemia and in autosomal

recessive sideroblastic anemia due to defects in the SLC25A38 transporter, the
erythrocyte protoporphyrin (PP) level is uniformly low because of reduced
protoporphyrin production consequent to defective ALAS2 enzyme activity and
apparent impaired import of the substrate glycine for ALAS2, respectively. A markedly
increased PP level (exclusively as free protoporphyrin) is characteristic in
protoporphyria. The erythrocyte PP is also increased in the rare variant with ataxia
(mainly as zinc protoporphyrin) [9] as well as in some cases without an identified
molecular defect(s) that may affect the pathway for heme synthesis.

Bone marrow examination — The bone marrow shows normoblastic erythroid

hyperplasia with poorly hemoglobinized cytoplasm in the developing red cell
precursors. Megaloblastic changes are uncommon, but may be found if folate
deficiency coexists. The diagnostic hallmark is the presence of ring sideroblasts that
are typically prominent at the late, non-dividing erythroblast stage (picture 5). As
noted above, the amount of iron in bone marrow macrophages is strikingly increased,
due to the presence of ineffective erythropoiesis (intramedullary hemolysis).

Molecular studies — Mutations in the erythroid-specific 5-aminolevulinate synthase

(ALAS2) gene define the X-linked form of congenital sideroblastic anemia, while
mutations in the SLC25A38 mitochondrial transporter gene specify an autosomal
recessive sideroblastic anemia. Mutations are found in the ABCB7 transporter gene in
X-linked sideroblastic anemia with ataxia, in the PUS1 and YARS2 genes in myopathy,
lactic acidosis and sideroblastic anemia syndrome, and in the SLC19A2 gene in
thiamine-responsive megaloblastic anemia syndrome. In Pearson syndrome
mitochondrial DNA deletions and rearrangements are typical. These are described in
more detail elsewhere. (See "Causes of congenital and acquired sideroblastic
anemias".)

Management — To achieve close to normal survival of patients with the non-

syndromic forms of congenital sideroblastic anemia, the treatment program must be
aimed at prevention of organ damage from the associated iron overload, as well as
control of the symptoms of anemia. Unlike cases of acquired clonal sideroblastic
anemia, a predisposition to leukemic evolution has not been observed in patients with
the congenital and acquired reversible forms.

Definitive cure is not readily available, although allogeneic hematopoietic cell

transplantation has been successful in seven reported patients [10-14], including
recovery from chronic graft versus host disease after orthotopic liver transplantation in
one of these patients [15]. Gene therapy as yet presents formidable challenges, due to
difficulty in transducing hematopoietic stem cells.

Anemia — In the X-linked form, the anemia may respond to pyridoxine supplements
in up to two thirds of cases; hemoglobin concentrations return to normal in about one-
third of the responders.

The morphologic red cell abnormalities improve variably, but very rarely completely
disappear [1,16]. Vitamin B6 (pyridoxine), in oral doses of 50 to 100 mg/day over and
above the estimated adult daily requirement of 1.5 to 2 mg/day are sufficient for a
maximal response; in some cases only 2 to 4 mg/day were found to be effective [17].
Maintenance treatment with vitamin B6 is necessary, as relapse follows within several
months after discontinuing treatment. If a concomitant folate deficiency is
documented, this should be replaced at the same time.

For severely anemic individuals, periodic transfusions are necessary to relieve

symptoms, and, for children, to allow normal growth and development. Transfusion of
red cells should be kept to a minimum as it accelerates the iron overload of these
disorders.

Iron overload — The associated iron overload requires treatment for optimal

prognosis, thereby minimizing or averting morbidity from parenchymal organ damage.
Based on the severity of iron overload (eg, serum ferritin >500 microg/L), best
documented by liver biopsy, an iron depletion program must be instituted. This is
accomplished in one of two ways: therapeutic phlebotomy or iron chelation. (See
"Pathophysiology and diagnosis of iron overload syndromes", section on 'Diagnosis'.)

 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
[18,19]. After initial de-ironing, maintenance phlebotomies are continued on
a regular basis for life, in order to prevent reaccumulation of iron. (See
"Treatment of hereditary hemochromatosis", section on 'Phlebotomy'.)
 Iron chelation therapy — 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 deferoxamine or
an oral iron chelating agent.

The siderophore deferoxamine is poorly absorbed from the gastrointestinal tract and
must be given parenterally. It avidly binds non-protein-bound, non-heme-bound iron
that is in a transit phase within cells to form ferrioxamine, which freely exits cells and
is readily excreted in urine and bile. Since its availability in the 1960s, clinical
experience with deferoxamine has been extensive, especially in the treatment of the
thalassemic syndromes [20]. Continuous infusion of the agent is necessary, and
effective iron excretion occurs with daily 12- to 24-hour infusions administered
subcutaneously or intravenously. The standard dose is 40 mg/kg per day. The goal of
chelation therapy is to maintain the serum ferritin concentration <500 microg/L (<500
ng/mL), but the progress of treatment may be best assessed with follow-up analysis of
hepatic iron content [20]. (See "Chelation therapy for iron overload states".)

Iron removal with deferoxamine is enhanced by ascorbate. However, large

supplements of ascorbate can cause acute cardiac toxicity by facilitating excessive
mobilization of ferritin iron; intake of the vitamin should therefore not exceed 200 mg
daily [21]. Adverse effects of deferoxamine are usually limited to local chemical skin
reaction and rare hypersensitivity, for which desensitization can be performed.
Auditory and visual toxicity (eg, cataracts) is most unlikely when the dose is not
excessive. However, patients on a chronic regimen should have periodic
ophthalmologic examination. There is some increased risk of infection with
mucormycosis and Yersinia with deferoxamine use.

The orally active tridentate iron chelator deferasirox (Exjade) has an efficacy similar to
deferoxamine [22,23]. The recommended daily dose is 20 mg/kg and can be increased
to 30 mg/kg. Adverse effects of the drug have been mainly skin rash, mild gastro-
intestinal complaints, and non-progressive serum creatinine increases [23]. Although
its long-term safety profile is not yet known, it appears to be emerging as the
preferred iron chelator. (See "Chelation therapy for iron overload states", section on
'Deferasirox'.)

The oral bidentate chelation agent deferiprone (Ferriprox) has been and continues to
be tested in clinical trials for long-term efficacy and safety as well as in combination
with deferoxamine [24,25]. The drug is used in Europe and Asia; in the United States
it can be obtained on an individual request basis from Apotex with IND approval. (See
"Chelation therapy for iron overload states", section on 'Deferiprone'.)

Risk of splenectomy — 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 [26-28]; similar
complications, although less severe, are reported in splenectomized patients with
thalassemia intermedia [29]. 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 in this disorder.
Information on the safety of partial splenectomy in this situation is not available.

CLONAL SIDEROBLASTIC ANEMIA — This disorder generally occurs in middle-aged

and older individuals, although younger persons including children are not spared. The
anemia develops insidiously and may be discovered during a routine examination or in
association with an unrelated complaint. Older individuals more often experience
symptoms of fatigue and angina, especially if there is coexisting coronary artery
disease. Apart from pallor, hepatosplenomegaly is found in one-third to one-half of
patients. With advanced iron overload, often after repeated transfusions, symptoms
and signs of liver decompensation, as well as heart failure and arrhythmia, may occur.

Since 1982 this disorder has been included in the FAB classification, and currently in
the WHO classification of the myelodysplastic syndromes (MDS) as refractory anemia
with ring sideroblasts (RARS); it has the best overall prognosis of all of the recognized
MDS variants (table 2 and table 3). It often tends to run an indolent course, but not
infrequently patients become transfusion dependent. (See "Clinical manifestations and
diagnosis of the myelodysplastic syndromes", section on 'Classification'.)

Based on a retrospective analysis of cytomorphological data in 94 patients, two types

of the disorder were proposed to be present, with different prognostic features [30]:
  A pure sideroblastic anemia (PSA), with dysplasia confined to the erythroid cell
lineage, now called RARS.
 A "true" myelodysplastic form with additional dysplastic features involving
granulopoiesis and/or megakaryopoiesis, now called RCMD-RS. (See "Clinical
manifestations and diagnosis of the myelodysplastic syndromes".)

Essentially identical findings were noted in a succeeding prospective study of 232 new
patients [31]. Overall survival at three years differed significantly for PSA and the
myelodysplastic form, at 77 and 56 percent, respectively. For patients with PSA,
survival was similar to that of age-matched controls, and the incidence of leukemic
transformation was nil [30,31]. In contrast, approximately 5 percent of patients with
RCMD-RS evolved to acute leukemia (table 3).

The RARS variant associated with thrombocytosis (RARS-T), which frequently has the
JAK2V617F mutation, appears to have a better prognosis than RARS [32].

Diagnosis — In women, the hematologic phenotype of PSA or RARS is often

indistinguishable from X-linked sideroblastic anemia; this latter disorder should
therefore be excluded. (See "Causes of congenital and acquired sideroblastic anemias",
section on 'X-linked sideroblastic anemia'.).

Complete blood count — The anemia is usually moderate and normocytic or

macrocytic, with a variable population of hypochromic cells on the blood smear.
Particularly characteristic are occasional siderocytes: hypochromic red cells with
basophilic stippling that stains positive for iron (ie, Pappenheimer bodies) (picture 6).

Leukocyte and platelet counts are usually within the normal range in patients with
RARS. The presence of moderate leukopenia and/or thrombocytopenia tends to be
associated with other myelodysplastic features, such as the pseudo-Pelger anomaly
(picture 7) or immature leukocytes in the peripheral blood. Leukocytosis and/or
thrombocytosis are least common, and reflect the presence of a myeloproliferative
process. (See "Overview of the myeloproliferative neoplasms".)

Erythrocyte protoporphyrin — The erythrocyte protoporphyrin is characteristically

increased, up to about 300 microg/dL (normal: 20 to 65). However, in some patients,
values have ranged from 1055 to 10,514 microg/dL, and some have experienced
photosensitivity [1,33]. Patients with these striking levels likely harbor a ferrochelatase
gene defect, and should be evaluated for the presence of late onset erythropoietic
protoporphyria. (See "Erythropoietic protoporphyria".)

Iron studies — Serum iron and ferritin levels reflect the commonly associated iron
overload, as in congenital sideroblastic anemia (see above) [34,35].
Bone marrow examination — Bone marrow aspiration shows the presence of
erythroid hyperplasia, commonly with mild megaloblastic changes. The marrow
macrophage iron content is increased and, in contrast to the congenital forms, ring
sideroblasts are evident at all stages of maturation; their presence establishes the
diagnosis (picture 5). The cytomorphologic findings as outlined above should allow one
to subclassify the condition as RARS, RARS-T, or RCMD-RS [30,31].

Notably, bone marrow cytogenetic abnormalities in patients with RARS are uncommon;
in one study chromosomal abnormalities known to be associated with an unfavorable
clinical course (eg monosomy 7, 7q- and complex aberrations) were only encountered
in the RCMD-RS group [30]. In the RARS-T subtype, the JAK2 V617F mutation is
frequent as in myeloproliferative disorders.

Management — Available treatment measures are supportive. Curative treatment

with hematopoietic cell transplantation, with the attendant risks, is considered an
option for younger individuals, as in the other myelodysplastic syndromes [36-38].

Pyridoxine supplementation is often prescribed but a response is not expected as it can

improve anemia only in patients with the congenital X-linked form of sideroblastic
anemia, owing to the causative ALAS2 deficiency in that disorder. (See "Causes of
congenital and acquired sideroblastic anemias", section on 'Molecular basis for
pyridoxine responsiveness'.) Associated folate deficiency is uncommon and should be
documented before folic acid is prescribed.

Erythropoietin and G-CSF — In a number of studies, it was observed that up to 50

percent of patients with myelodysplastic syndromes respond to the combination of
these two hematopoietic growth factors, and a response generally occurs in one to two
months [39-43]:

 Response to erythropoietin (EPO) is more likely if the serum EPO level is not
raised commensurate with the level of anemia [43,44], and doses up to
10,000 to 15,000 units per day may be required to obtain a response
[author's observations].
 The addition of granulocyte colony-stimulating factor (G-CSF) provides a
synergistic effect, especially after prolonged administration [39,42].

Darbepoetin, the longer-acting version of EPO, appears to have similar efficacy

[45,46]. While symptoms of anemia are relieved and any transfusion dependence is
reduced or eliminated by this therapy in responding patients, overall patient survival
has not been affected [42]; it appears to be improved in patients with a low
transfusion need [47]. (See "Treatment and prognosis of the myelodysplastic
syndromes", section on 'Hematopoietic growth factors'.)

Chemotherapeutic agents — Studies have evaluated various drug regimens for the

myelodysplasias that also contained small numbers of patients in the sideroblastic
anemia category. The drugs used have included the hypomethylating agents 5-
azacytidine and decitabine, anti-tumor necrosis factor (TNF) fusion protein
(etanercept), antithymocyte globulin (ATG), thalidomide and its derivative
lenalidomide, and valproic acid [48-53]. Major responses with improved erythropoiesis
or hematopoiesis have been seen in <50 percent. (See "Treatment and prognosis of
the myelodysplastic syndromes", section on 'Treatment guidelines'.)

Transfusion — If anemia is symptomatic or progresses to a symptomatic stage,

regular red cell transfusions are necessary, especially in the presence of advanced age
and/or other comorbid conditions, such as coronary artery disease.

Removal of excess iron — Phlebotomy or iron chelation (eg, deferoxamine,

deferasirox) can be used to control the iron overload, as outlined for congenital
sideroblastic anemia (see 'Iron overload' above).

Transfusional iron overload is associated with reduced survival [35,54], and evidence is
emerging for improved clinical outcomes with iron chelation therapy [55]. Guidelines
have been presented for iron chelation therapy in patients with International
Prognostic Scoring System (IPSS) low and intermediate-1 risk MDS [55,56]; it is
advised in patients dependent on regular transfusions (eg, after approximately 20
units of blood have been given), with treatment decisions individualized for each
patient. (See "Treatment and prognosis of the myelodysplastic syndromes", section on
'Supportive care'.)

Risk of splenectomy — Similar to patients with congenital sideroblastic anemia,

splenectomy should be avoided at all costs (see 'Risk of splenectomy' above).

ACQUIRED REVERSIBLE SIDEROBLASTIC ANEMIAS — In this category, the

clinical setting characterizes the problem and defines the laboratory studies required
for the diagnosis. The anemia is invariably corrected upon removal of the precipitating
cause. Iron overload is not observed.

Sideroblastic anemia associated with alcoholism — The presence of the ring

sideroblast abnormality contributes to the severity of anemia in an alcoholic patient,
and usually reflects a more advanced stage of a multi-factorial anemia (eg, associated
liver disease, folate deficiency, blood loss, hemolysis, hypersplenism), including the
direct effects of alcohol on hematopoiesis. (See "Alcohol abuse and hematologic
disorders", section on 'Bone marrow examination'.)

The sideroblastic change occurs in approximately one-third of patients [57] and is

evident in a dimorphic erythrocyte pattern, as well as the presence of an occasional
siderocyte in the peripheral blood. Marrow ring sideroblasts typically represent late
erythroblasts. Marrow iron stores are usually increased, as are the serum transferrin
saturation and the serum ferritin level, unless concomitant iron deficiency is present.

Withdrawal of alcohol is followed by disappearance of ring sideroblasts within a few

days to two weeks [58]. Recovery from the anemia tends to occur over several weeks.
The rate of improvement of the anemia depends on the presence of other erythroid
defects induced by alcohol [59], as well as any associated medical illness affecting
erythropoiesis. A more prompt recovery phase may be associated with a brisk
reticulocytosis and erythroid hyperplasia of the bone marrow, a picture that might be
otherwise mistaken as an episode of hemolytic anemia.

Drug-induced sideroblastic anemia — Isoniazid and chloramphenicol have served

as the prototype drugs which produce a sideroblastic anemia. Cycloserine and
pyrazinamide have also been implicated in a few patients [59].

Isoniazid — The relative incidence of anemia in relation to the extensive use of

isoniazid (INH) appears to be quite low. However, the presence of another hematologic
disorder may render certain individuals more susceptible to INH-induced anemia. In
one study, ring sideroblasts or increased erythroblast iron was found in 58 percent of
all patients treated with INH for tuberculosis [60].

Anemia occurs from 1 to 10 months after institution of isoniazid therapy. The anemia is

moderately severe (hematocrit 20 to 26 percent), the MCV is usually reduced, with
dimorphic red cell morphology and prominent hypochromia and microcytosis [61]. Ring
sideroblasts are invariably present in the bone marrow. Serum pyridoxal
concentrations were subnormal in most patients [62,63]. Increased transferrin
saturation is also consistent with the abnormality.

The anemia is promptly and fully reversed on withdrawal of the drug or by

administering large doses of pyridoxine (up to 200 mg/day PO), while continuing the
drug.

Chloramphenicol — Chloramphenicol appears to regularly produce the ring

sideroblast abnormality in all individuals, depending on the dose and duration of its
administration [64,65]. In addition, this agent suppresses erythropoiesis by producing
a hypoproliferative state.
The anemia may reach moderately severe levels. Marrow study reveals variable
degrees of hypocellularity and ring sideroblasts as well as prominent vacuolization of
early erythroid precursors [66,67]. Reticulocytopenia and increased serum iron levels
are characteristic. The anemia and associated morphologic abnormalities disappear
upon withdrawal of the drug.

Copper deficiency — Copper depletion occurs under several circumstances. It has

developed after gastrectomy [68], after prolonged parenteral nutrition [69,70] or
forced enteral feeding if copper was not included in the formulations [71,72], in
association with intestinal malabsorption [73], as well as following the use of a copper-
chelating agent [74]. Copper deficiency with anemia may also occur after prolonged
ingestion of zinc supplements [75,76]. (See "Causes of congenital and acquired
sideroblastic anemias", section on 'Zinc toxicity'.) Similarly, zinc toxicity with resulting
copper deficiency has developed from ingestion of zinc-containing coins [77-80].
Clinical findings were limited to symptoms and signs of anemia.

It is now well established that copper deficiency anemia is often associated with a

variety of neurologic manifestations, including CNS demyelination, peripheral
neuropathy, optic neuropathy, or, most often, myeloneuropathy; this appears to have
been overlooked in the past [81-87]. Some patients have had prior gastrointestinal
operations (eg, gastrectomy, bariatric surgery), celiac disease, or another possible
malabsorption disorder [87]. Excess zinc ingestion had occurred in only a few. Chronic
use of large amounts of denture cream containing zinc has been recognized as another
cause of zinc toxicity and clarified the origin of high zinc levels in some patients with
this syndrome [88,89]. Apart from these identified causes of copper deficiency, in
many cases an etiology was not found.

Diagnosis — Anemia is progressive in most cases and may be profound, with

hemoglobin levels as low as 3.5 g/dL [75]. The MCV is normal or slightly increased, but
hypochromic-microcytic red cells are detectable on the blood smear. Granulocyte levels
are strikingly reduced, usually to less than 1000/microL, while the platelet count is
usually normal. Pancytopenia has been reported in some cases. The bone marrow is
variably cellular; vacuolization of early erythroid and granulocytic precursors is a
common finding [86,90]. Moderate numbers of ring sideroblasts are observed and
plasma cells often contain prominent hemosiderin [87,90].

Serum iron levels and transferrin saturation are normal. The serum copper and
ceruloplasmin levels are uniformly low. In cases of zinc-induced copper deficiency,
serum zinc levels are increased two- to three-fold. Serum zinc concentrations were
 also increased in some patients with copper deficiency and neurologic disease without
identifiable excess zinc intake [81,86,91], as were urine zinc levels when measured.

Thus, normocytic or macrocytic anemia with neutropenia and marrow ring sideroblasts
with or without neurologic abnormalities would nearly always indicate a
copper deficiency state and not myelodysplastic syndrome [86,90].

Management — The copper deficit is readily corrected with parenteral or oral copper

preparations that provide 2.0 mg of elemental copper per day and the hematologic
abnormalities return to normal in less than two months [70,75,81,86,90,91]. However,
this usual dose of copper may not be sufficient for all patients as relapse has occurred
[92], and long-term follow-up is advised for all patients. Hematologic recovery may
occur following discontinuation of excess zinc intake alone. Neurologic deficits, when
present, may improve or only stabilize with continued copper supplementation
[81,86,87,90,91].

Lead poisoning — This condition, which is associated with disordered heme

metabolism, is often listed in textbooks as a cause of sideroblastic anemia. However, it
is the author's opinion that lead poisoning is not associated with sideroblastic changes.
On the other hand, lead poisoning should be considered in the differential diagnosis of
hypochromic microcytic anemia with or without basophilic stippling, and may therefore
be confused with the sideroblastic anemias.

The subject of lead poisoning in adults and children is discussed separately. (See
"Adult lead poisoning" and "Childhood lead poisoning: Clinical manifestations and
diagnosis" and "Childhood lead poisoning: Exposure and prevention" and "Childhood
lead poisoning: Treatment".)

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93. Red cell size distribution curves in hereditary

sideroblastic anemia
 94.
95. (Top panel) Size distribution curve from a 28-year-old man with autosomal
recessive congenital sideroblastic anemia (Hb, 6.7 g/dL; MCV, 65 fL; RDW, 35).
The pattern indicates a broad population of red cells, varying markedly in size,
with the majority of the cells being microcytic.
(Bottom panel) Size distribution curve from a 60-year-old woman with X-linked
sideroblastic anemia (Hb, 9.9 g/dL; MCV, 93 fL; RDW, 14). It indicates the
presence of two populations of red cells: one is comprised of normocytic to
macrocytic red cells (black arrow) derived from precursors expressing the
normal ALAS2, while a lesser population contains only microcytic red cells (red
arrow) derived from precursors expressing the mutant ALAS2.
96. Iron overload in sideroblastic anemia
 97.
98. Liver biopsy sections from a 26-year-old man with autosomal
recessive congenital sideroblastic anemia and moderate iron overload.
(Top panel) Hematoxylin and eosin stain.
(Bottom panel) Prussian blue (iron) stain.
99. Courtesy of Sylvia Bottomley, MD.