Clinical aspects, diagnosis, and treatment of the sideroblastic anemiasAuthorSylvia S Bottomley, MDSection EditorStanley L Schrier, MDDeputy EditorStephen A Landaw, MD, PhDLast 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.