Sideroblastic Anemias

Updated: Nov 18, 2015
  • Author: Muhammad A Mir, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
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Overview

Background

Adult human bone marrow synthesizes 4 X 1014 molecules of hemoglobin every second. [1] 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.

In some instances, both the synthesis of heme and the incorporation of iron can be altered, and the result is a porphyria with sideroblasts (eg, erythropoietic protoporphyria). [2, 3]

Sideroblastic anemia is primarily a laboratory diagnosis, made on the basis of bone-marrow examination with Prussian blue stain. The history and physical examination can provide certain clues, but they usually do not pin down the exact diagnosis. Workup may include a complete blood count (CBC), peripheral smear, iron studies (eg, ferritin and total iron-binding capacity [TIBC]), bone marrow aspiration and biopsy, and other studies as appropriate.

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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 (see the image below).

Ring sideroblast. Ring sideroblast.

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 (see the image below).

Heme synthesis. Heme synthesis.

Sideroblastic anemias may be either congenital or acquired (see the image below).

Sideroblastic anemias: etiologic classification. D Sideroblastic anemias: etiologic classification. DIDMOAD = diabetes insipidus, diabetes mellitus, optic atrophy, deafness.

Congenital sideroblastic anemias

Congenital sideroblastic anemias generally present with lower hemoglobin and more microcytosis than myelodysplastic syndrome and are usually associated with higher serum iron levels than myelodysplastic syndrome. [4]

Of the congenital sideroblastic anemias, X-linked sideroblastic anemias are further divided into pyridoxine-responsive (>50%) and pyridoxine-resistant subtypes.

In the pyridoxine-responsive subtype, point mutations on the X chromosome have been identified that result in a δ-amino levulinic acid synthase (ALAS-2) with very low enzymatic activity. [5] This development impairs the first crucial step in the heme synthesis pathway, the formation of δ-amino levulinic acid, resulting in anemia despite intact iron delivery to the mitochondrion and with a lack of heme in which iron is to be incorporated in the final step of this pathway. This is the most common of the hereditary sideroblastic anemias, followed by mitochondrial transporter defects such as SLC25A38 gene mutation discussed below. [6]

A prototype of pyridoxine-resistant X-linked sideroblastic anemia is the ABC7 gene mutation. [7, 8] ABC-7 is an adenosine triphosphate (ATP)-dependent transporter protein involved in the cytosolic transfer of iron-sulfur complexes. In contrast to pyridoxine-responsive sideroblastic anemia, the ABC7 defect has a nonprogressive cerebellar ataxia component with diminished deep-tendon reflexes, incoordination, and elevated free erythrocyte protoporphyrin. [9]

Autosomal recessive sideroblastic anemia has been described in conjunction with mitochondrial myopathy and lactic acidosis in Jews of Persian descent, resulting from pseudouridine synthase-1 (PUS-1) mutations. [10] Pseudouridine is a nucleoside isomer of uridine that is used as a building block in mitochondrial RNA. The defect results in impaired oxidative phosphorylation, which explains the muscle and nerve manifestations, and sideroblastic anemia due to dysfunctional mitochondria, the center of heme synthesis.

An autosomal dominantly inherited form also exists but is extremely rare. [11]

Pearson (marrow-pancreas) syndrome, described in 1979, [12] is a juvenile multisystem disorder caused by deletions in mitochondrial DNA (mtDNA) and manifested as severe, refractory sideroblastic anemia, neutropenia, vacuolated cells in bone-marrow precursors, exocrine pancreas insufficiency, malabsorption, and growth failure. [13]

DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome is associated with sideroblastic anemia that is responsive to vitamin B-1 (thiamine). The proposed etiology of DIDMOAD syndrome is an inherited defect in thiamine metabolism. [14]

Acquired sideroblastic anemias

Acquired sideroblastic anemias can be classified into clonal (myelodysplastic syndrome) and nonclonal (metabolic) types.

Of the numerous classes of myelodysplastic syndrome in the World Health Organization 2008 classification updated in 2009, 2 represent sideroblastic anemias (refractory anemia with ring sideroblasts [RARS] and refractory cytopenia with multilineage dysplasia [RCMD]). Refractory anemia with ring sideroblasts with thrombocytosis variant (RARS-T; JAK2 v617f mutation predominant), which has both sideroblastic anemia and thrombocytosis, is an additional consideration as a distinct entity. [15] Half of RARS-T patients carry the JAK2 mutation. [16] . RARS carries a good prognosis, with no pancytopenia, very low chance of transforming into acute myeloid leukemia, and 5-year survival of greater than 50%, contrary to RCMD. [17] See the image below.

The World Health Organization 2008 of myelodysplastic syndrome is as follows:

  • Refractory anemia – Anemia only, with less than 5% blasts in bone marrow
  • RARS, RARS-T (not listed as a separate category in original classification) – Greater than 15% ring sideroblasts, with less than 5% blasts in bone marr
  • RCMD - Anemia with thrombocytopenia, neutropenia, or both, with less than 5% blasts in bone marrow
  • Myelodysplastic syndrome unclassifiable (not fitting in any other categories) – Neutropenia, thrombocytopenia, or both, with less than 5% blasts in bone marrow
  • 5q myelodysplastic syndrome (with isolated 5q deletion) – Anemia without thrombocytopenia, with less than 5% blasts in bone marrow
  • Refractory anemia with excess blasts 1 – Cytopenias with blasts, 5% in peripheral blood, with less than 5-9% blasts in bone marrow
  • Refractory anemia with excess blasts 2 – Cytopenias and blasts in peripheral blood, with less than 10-19% blasts in bone marrow

Recently, a new mutation, SF3B1,in the spliceosome apparatus, which catalysis mRNA splicing, was noted to have a predominant presence among patients with ring sideroblasts. While about half of the patients with myelodysplastic syndrome exhibit spliceosome mutations, up to 80% of those with RARS or RARS-T had SF3B1 mutations. [18] Contrary to its poor prognostic significance in chronic lymphocytic leukemia, in MDS this mutation appears to lower transformation into acute leukemia. [19] This mutation is not found in congenital sideroblastic anemias. [4]

Interestingly, the more numerous the sideroblasts, the lower the risk of progression. [20] Ring sideroblasts, as a morphologic finding, may also be present in patients with other forms of myelodysplastic syndrome.

Copper deficiency, which can occur as a part of malabsorption, [21] nephrotic syndrome (loss of ceruloplasmin), [22] gastric surgery, [23] or as a consequence of excessive zinc intake (supplements), [24] can masquerade as myelodysplastic syndrome with sideroblastic anemia and leukopenia. [25] . Low serum copper and ceruloplasmin are typical. Copper replacement reverses the hematologic abnormalities. [26]

Vitamin B-6 (pyridoxine) forms pyridoxal phosphate, which acts as a coenzyme in the first, rate-limiting step in heme formation catalyzed by δ-ALAS. [27] Deficiency of vitamin B-6 causes sideroblastic anemia.

Lead poisoning has been known to cause sideroblastic anemia by inhibiting several enzymes involved in heme synthesis, including δ-aminolevulinate dehydratase, coproporphyrin oxidase, and ferrochelatase. [28]

Excessive alcohol consumption can cause several forms of anemia through nutritional deficiencies (eg, of iron or folate), hemolysis, splenic sequestration due to liver cirrhosis, direct bone marrow toxicity to erythroid precursors, [29] inhibition of pyridoxine, [30] lead contamination of wine, [31] and inhibition of ferrochelatase enzyme during heme formation. [32]

Drugs reported to cause sideroblastic anemia include diverse classes, such as antibiotics (eg, chloramphenicol, [33] fusidic acid, [34] linezolid, [35] tetracycline, [36] isoniazid [37] ), hormones (eg, progesterone [38] ), pain medicines (eg, phenacetin [39] ), copper chelating agents (eg, penicillamine [40] and trientine [41] ), and chemotherapy agents (eg, busulfan, melphalan). [42] In most cases, stopping the drug reverses the sideroblastic changes.

Pure sideroblastic anemia, although similar in some ways to RARS, differs from RARS by being less likely to transform to acute leukemia. [43]

Hypothermia has been reported to cause sideroblastic anemia with a marked reduction in normoblastic erythropoiesis and thrombocytopenia with normal megakaryocytes. The changes reverse in most cases with the normalization of temperature. [44]

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Etiology

Congenital causes of sideroblastic anemia include the following:

  • δ-ALAS mutation
  • ABC7 mutation
  • PSU1 mutation
  • Pearson syndrome (mitochondrial protein defects)
  • DIDMOAD syndrome
  • Mitochondrial SLC25A38 usually presenting in children
  • SCL19A2 (thiamine transporter) gene defects [45, 4]
  • Glutaredoxin 5 defects [46]
  • Erythropoietic protoporphyria (ferrochelatase deficiency)

Acquired causes of sideroblastic anemia include the following:

  • Myelodysplastic syndrome
  • SF3B1 - Splicing factor 3B subunit 1 mutations [47, 48, 49]
  • Nutritional deficiencies (copper, vitamin B-6)
  • Lead poisoning (disputed by some authorities as a cause)
  • Zinc overdose
  • Alcohol
  • Drugs (eg, antituberculous agents, antibiotics, progesterone, chelators, phenacetin, busulfan)
  • Hypothermia
  • Idiopathic
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Epidemiology

In 25 bone marrow biopsies of children younger than 13 years from Atlanta, Georgia (United States), with anemia, the prevalence of ringed sideroblasts was 8%. [50]

In France, the prevalence of ringed sideroblasts was 57% in patients with primary MDS. [51] In the United Kingdom, amongst healthy volunteers undergoing bone marrow biopsy, siderotic granules (not ring sideroblasts) were present in 29% of men and 19% of women. [52]

Although usually manifested in childhood, congenital X-linked sideroblastic anemia due to ALAS mutation can remain undiagnosed and then present late in the fourth to eighth decades of life. [53, 54] The median age of occurrence of primary acquired sideroblastic anemia is 74 years. [55]

X-linked recessive types of sideroblastic anemia occur more commonly in males. A female would have to inherit 1 abnormal chromosome from each parent to acquire the disease. Progesterone and pregnancy have been reported to induce relapse of sideroblastic anemia. [56]

No racial predominance is reported in sideroblastic anemia.

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Prognosis

The prognosis of sideroblastic anemia is highly variable. Reversible causes such as alcohol and drugs do not appear to carry long-term sequelae. On the other hand, patients with transfusion dependence, those with conditions unresponsive to pyridoxine and other therapies, and those with MDS that develops into acute leukemia have a less bright prognosis.

In congenital sideroblastic anemias, mitochondrial abnormalities may produce neuromuscular dysfunction. In acquired sideroblastic anemias, mortality and morbidity is obviously variable as some of the causes are reversible. The anemia itself is usually moderate, with hematocrit in the 20-30% range. [57] In idiopathic sideroblastic anemia with MDS, median survival is 38 months, as compared with 60 months in pure sideroblastic anemia (with dyserythropoiesis only, without abnormal megakaryocytic and granulocytic precursors). [58]

Major causes of death in cases of sideroblastic anemia are secondary hemochromatosis from transfusions and leukemia. The patients who die of acute leukemia tend to have a more severe anemia, a lower reticulocyte count, an increased transfusion requirement, and thrombocytopenia.

Thrombocytosis appears to be a relatively good prognostic sign. [59] Patients with no need for blood transfusions are very likely to be long-term survivors, whereas those who become transfusion dependent are at risk of death from the complications of secondary hemochromatosis. [60]

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Patient Education

Genetic counseling and an antenatal diagnosis of sideroblastic anemia have in recent years become of practical relevance to families with known cases of congenital sideroblastic anemia. Careful documentation of the clinical outcome of these cases and of other family members is invaluable. [61]

For patient education resources, see the Blood and Lymphatic System Center, as well as Anemia.

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