Sideroblastic Anemias

Updated: Sep 10, 2019
  • Author: Muhammad A Mir, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
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Overview

Practice Essentials

[1] The sideroblastic anemias (SAs) are a group of inherited and acquired bone marrow disorders characterized by pathological iron accumulation in the mitochondria of erythroid precursors. Abnormal, iron-laden mitochondria appear to encircle erythroblast nuclei, giving rise to the defining morphological feature of the ring sideroblast (RS). [2] The detection of bone marrow ring sideroblasts can be seen in a variety of clonal hematological and non-clonal disorders. Clonal conditions associated with RS include myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and MDS/MPN overlap syndromes. [3]  Non-clonal conditions include alcoholism, lead poisoning, zinc overdose, copper or pyridoxine deficiency, and congenital sideroblastic anemias (CSA).

Congenital sideroblastic anemias (CSAs) can be attributed to mutations in 1 of 3 mitochondrial pathways: heme synthesis, iron-sulfur cluster biogenesis and protein synthesis.

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.

Treatment of sideroblastic anemia may include removal of toxic agents; administration of pyridoxine, thiamine, or folic acid; transfusion (along with antidotes if iron overload develops from transfusion); other medical measures; or bone marrow or liver transplantation.

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Background

Adult human bone marrow synthesizes 4 × 1014 molecules of hemoglobin every second. [4]  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 anemia.

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). [5, 6]

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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 the 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.

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. [7]

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. [8] 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. [9]

A prototype of pyridoxine-resistant X-linked sideroblastic anemia is the ABC7 gene mutation. [10, 11] 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. [12]

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. [13] 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. [14]

Pearson (marrow-pancreas) syndrome, described in 1979, [15] 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. [16]

Nonclonal acquired sideroblastic anemias

Copper deficiency, which can occur as a part of malabsorption, [17]  nephrotic syndrome (loss of ceruloplasmin), [18]  gastric surgery, [19]  or as a consequence of excessive zinc intake (supplements), [20]  can masquerade as myelodysplastic syndrome with sideroblastic anemia and leukopenia. [21] . Low serum copper and ceruloplasmin are typical. Copper replacement reverses the hematologic abnormalities. [22]

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. [23]  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. [24]

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, [25]  inhibition of pyridoxine, [26]  lead contamination of wine, [27]  and inhibition of ferrochelatase enzyme during heme formation. [28]

Drugs reported to cause sideroblastic anemia include diverse classes, such as the following:

  • Antibiotics (eg, chloramphenicol, [29]  fusidic acid, [30]  linezolid, [31]  tetracycline, [32]  isoniazid [33] )
  • Hormones (eg, progesterone [34] )
  • Pain medicines (eg, phenacetin [35] )
  • Copper chelating agents (eg, penicillamine [36]  and trientine [37] )
  • Chemotherapy agents (eg, busulfan, melphalan) [38]  

In most cases of drug-induced sideroblastic anemia, stopping the drug reverses the sideroblastic changes.

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. [39]

Clonal acquired sideroblastic anemias

In the 2016 revised World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia, two myeloid neoplasms synonymous with the presence of bone marrow RS were reclassified.  Refractory anemia with ring sideroblasts (RARS) is now classified under myelodysplastic syndrome with ring sideroblasts (MDS-RS) and RARS with thrombocytosis (RARS-T) is now called MDS/MPN with RS and thrombocytosis (MDS/MPN-RS-T). [40]

The change in the classification of MDS to include MDS-RS is based largely on the link between ring sideroblasts and an SF3B1 mutation, which appears to be an early event in MDS pathogenesis, manifests a distinct gene expression profile, and correlates with a favorable prognosis. Contrary to its poor prognostic significance in chronic lymphocytic leukemia, in MDS this mutation appears to lower transformation into acute leukemia. [41] This mutation is not found in congenital sideroblastic anemias. [7]  Recent studies have shown that in cases of MDS with any ring sideroblasts, the actual percentage of ring sideroblasts is not prognostically relevant. [42]

MDS-RS cases will be subdivided into cases with single lineage dysplasia (MDS-RS SLD) which was previously classified as refractory anemia with ring sideroblasts; and cases with multilineage dysplasia (MDS-RS MLD) which were previously classified as refractory cytopenia with multilineage dysplasia. [3]

MDS/MPN-RS-T is also frequently associated with mutations in the spliceosome gene SF3B1 and is often comutated with JAK2 V617F or less frequently (< 10%) with CALR, or MPL genes. [43]  

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Etiology

Nonclonal sideroblastic anemia

The most common form of congential sideroblastic anemia (CSA) is caused by mutation of erythroid-specific 5-aminolevulinate synthase (ALAS2), the first enzyme of heme synthesis in erythroid cells. [7]  Other CSAs include SLC25A38 related sideroblastic anemia  [44] , glutaredoxin 5 (GLRX5) related sideroblastic anemia [45] , and X-linked sideroblastic anemia with ataxia-ABCB7 mutations.

The syndromic CSA phenotypes include:

  • Mitochondrial myopathy with lactic acidosis and sideroblastic anemia (MLASA) caused by PUS1 mutation  [46]
  • Sideroblastic anemia, B cell immunodeficiency, periodic fevers, and developmental delay (SIFD) caused by TRNT1 mutation
  • Pearson marrow-pancreas syndrome (PMPS)  [16]
  • Thiamine-responsive megaloblastic anemia syndrome (TRMA) caused by SLC19A2 mutation [44, 47]

Congenital sideroblastic anemia caused by respiratory insufficiency and loss of complex I stability and activity in patient-derived fibroblasts due to NDUFB11 mutations has been reported. [2]

Causes of nonclonal acquired sideroblastic anemia include the following:

  • Nutritional deficiencies (copper, vitamin B-6)
  • Lead poisoning 
  • Zinc overdose
  • Alcohol
  • Drugs (eg, antituberculous agents, antibiotics, progesterone, chelators, phenacetin, busulfan)
  • Idiopathic

Clonal sideroblastic anemia

Clonal conditions associated with ring sideroblasts (RS) include myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and MDS/MPN overlap syndromes. The WHO classification of these conditions are as follows [40, 3] :

Clonal RS myelodysplastic syndromes (MDSs) 

  • MDS with ring sideroblasts and single lineage dysplasia (MDS-RS SLD)
  • MDS with ring sideroblasts and multilineage dysplasia (MDS-RS-MLD)
  • MDS with excess blasts and ring sideroblasts
  • MDS-U with ring sideroblasts

Clonal RS​ myeloproliferative neoplasms (MPNs) 

  • Essential thrombocythemia with ring sideroblasts
  • Primary myelofibrosis with ring sideroblasts

Clonal RS MDS/MPN overlap syndromes 

  • MDS/MPN with ringed sideroblasts and thrombocytosis (MDS/MPN-RS-T)
  • Chronic myelomonocytic anemia with ring sideroblasts
  • Unclassified MDS/MPN with ring sideroblasts
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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%. [48]

In France, the prevalence of ringed sideroblasts was 57% in patients with primary MDS. [49] In the United Kingdom, among healthy volunteers undergoing bone marrow biopsy, siderotic granules (not ring sideroblasts) were present in 29% of men and 19% of women. [50]

Although usually manifesting 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. [51, 52] The median age of occurrence of primary acquired sideroblastic anemia is 74 years. [53]

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. [54]

No racial predominance is reported in sideroblastic anemia.

 

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Prognosis

The prognosis of patients with sideroblastic anemia is highly variable. Cases with 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. [55] 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). [56]

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. [57] 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. [58]

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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. [59]

For patient education resources, see Anemia.

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