Sideroblastic Anemias

Adult human bone marrow synthesizes 4 × 1014 molecules of hemoglobin every second.[5]  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).[6, 7]

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).

Ringed sideroblast.

Under normal circumstances, this iron would have been used to make heme. The process occurs only in the bone marrow, because mature erythrocytes lack mitochondria, the nexus of heme synthesis (see the image below).

Heme synthesis pathway.

Congenital sideroblastic anemias

Congenital sideroblastic anemias generally involve lower hemoglobin levels, more microcytosis, and higher serum iron levels compared with myelodysplastic syndrome.[8]

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.[9] 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.[10]

A prototype of pyridoxine-resistant X-linked sideroblastic anemia is the ABC7 gene mutation.[11, 12] 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.[13]

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.[14] 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.[15]

Pearson (marrow-pancreas) syndrome, described in 1979,[16] 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.[17]

Nonclonal acquired sideroblastic anemias

Copper deficiency, which can occur as a part of malabsorption,[18]  nephrotic syndrome (loss of ceruloplasmin),[19]  gastric surgery,[20]  or as a consequence of excessive zinc intake (supplements),[21]  can masquerade as myelodysplastic syndrome with sideroblastic anemia and leukopenia.[22] . Low serum copper and ceruloplasmin are typical. Copper replacement reverses the hematologic abnormalities.[23]

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.[24]  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.[25]

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,[26]  inhibition of pyridoxine,[27]  lead contamination of wine,[28]  and inhibition of ferrochelatase enzyme during heme formation.[29]

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

• Antibiotics (eg, chloramphenicol, ^[30]  fusidic acid, ^[31]  linezolid, ^[32]  tetracycline, ^[33]  isoniazid ^[34] )
• Hormones (eg, progesterone ^[35] )
• Pain medicines (eg, phenacetin ^[36] )
• Copper chelating agents (eg, penicillamine ^[37]  and trientine ^[38] )
• Chemotherapy agents (eg, busulfan, melphalan) ^[39]  

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.[40]

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).[41]

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.[42] This mutation is not found in congenital sideroblastic anemias.[8]  Recent studies have shown that in cases of MDS with any ring sideroblasts, the actual percentage of ring sideroblasts is not prognostically relevant.[43]

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.[4]

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.[44]  

Non-clonal sideroblastic anemia

The most common form of congenital sideroblastic anemia (CSA) is caused by mutation of erythroid-specific 5-aminolevulinate synthase (ALAS2), the first enzyme of heme synthesis in erythroid cells.[8] Other CSAs include SLC25A38-related sideroblastic anemia,[45] glutaredoxin 5 (GLRX5)–related sideroblastic anemia,[46] and X-linked sideroblastic anemia with ataxia–ABCB7 mutations.

The syndromic CSA phenotypes include the following:

• Mitochondrial myopathy with lactic acidosis and sideroblastic anemia (MLASA) caused by PUS1 mutation  ^[47]
• Sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) caused by  TRNT1 mutation
• Pearson marrow-pancreas syndrome (PMPS)  ^[17]
• Thiamine-responsive megaloblastic anemia syndrome (TRMA) caused by  SLC19A2 mutation ^{[45, 48]}

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.[3]

Causes of non-clonal 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 is as follows[41, 4] :

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, unclassifiable, 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

Non-syndromic CSA

This type of CSA is a form of SA that will present as SA alone rather than as part of a clinical syndrome. The various types include the following:

1. SIDBA1 is due to various forms of mutations such as missense, nonsense, and promoter/enhanger region mutations. ^[10]  All the mutations within this class show an X-linked inheritence pattern. ALAS2 is the gene most commonly implicated in this type of non-syndromic CSA.
2. SIDBA2 is caused by nonsense, frameshift, and missense mutations in SLC25A38, ^[45] which is needed to transport glycine into the mitochondria. The condensation of glycine with succinyl-coenzyme A (succinyl-CoA) to produce 5-aminolevulinate (ALA) is the first enzymatic step in heme biosynthesis. Thus, the mutations in SLC25A38 result in decreased production of heme.
3. SIDBA3 is due to a mutation in the gene GLRX5. This type of SA is very rare, having been reported in only two families to date. It is caused by a homozygous mutation that interferes with the splicing of GLRX5 mRNA, thereby reducing the gene's ability to produce iron-sulfur clusters, which are transporters than help move iron into the cytosol of the mitochondria during heme synthesis. ^[49]
4. SIDBA4 is caused by a mutation of HSPA9. Various mutations occur as in previous types including missense, nonsense, frameshift, and in-frame deletion mutations. The absence of HSPA9 in erythroid cell lines is reported to inhibit the differentiation of erythroid cells

Syndromic CSA

This type of CSA presents as part of a clinical syndrome.

1. XLSA/A is caused by a mutation in the ATP-binding cassette transporter (ABCB7). ABCB7 is involved in iron-sulfur cluster biogenesis, which helps to transport iron to the cytosol during heme production. A missense mutation in this gene leads to X-linked sideroblastic anemia with cerebellar ataxia. ^[49]
2. PMPS is due to a deletion of mitochondrial DNA. This causes a defect of the respiratory chain of the mitochondria, ^[50] which leads (through an unclear mechansim) to refractory sideroblastic anemia and exocrine pancreatic insufficiency. ^[16]
3. TRMA is caused by a mutation of the SLC19A2 gene, which codes for thiamine transporter 1, a protein located on the cell surface that works to bring thiamine into the cell. Thiamine is needed for the production of succinyl CoA, and deficient thiamine leads to megaloblastic anemia, diabetes mellitus, and deafness. ^[49]
4. MLSA1 is due to a missense mutation of PUS1, which helps in the translation of the respiratory chain in the mitochondria. It is not known why it causes sideroblastic anemia. ^[49]
5. MLSA2 is due to a mutation in the YAR2 gene, which encodes mitochondrial tyrosyl transfer RNA synthase.  The cause of sideroblastic anemia is also unknown with this type. ^[49]
6. SFID is due to a mutation of the TRNT1 gene, which encodes CCA-adding transfer RNA nucleotidyltransferase. The pathology of sideroblastic anemia in this disorder is unknown. ^[49]
7. NDUFB11 deficiency is due to a deletion of 3 nucleotides in the NDUFB11 gene, leading to phenylalanine deletion in the NDUFB protein and causing normocytic sideroblastic anemia and lactic acidosis. ^[51]

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%.[52]

In France, the prevalence of ringed sideroblasts was 57% in patients with primary MDS.[53] 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.[54]

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.[55, 56] The median age of occurrence of primary acquired sideroblastic anemia is 74 years.[57]

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.[58]

No racial predominance is reported in sideroblastic anemia.

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.[59] 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).[60]

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.[61] 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.[62]

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.[63] . 

For patient education resources, see Anemia.

The following clinical history features are suggestive of sideroblastic anemia:

• Incoordination (cerebellar symptoms)
• Failure of growth
• Fatigue
• Diarrhea (malabsorption)
• History of exposure to cold for prolonged periods
• Family history of mitochondrial disease and anemia
• Medication history of antibiotics, antituberculous agents, chelators, or chemotherapy
• Ingestion of supplements, especially zinc
• Prolonged dependence on parenteral nutrition, with insufficient replacement of copper
• Long-term dialysis with higher than normal zinc levels in dialysis fluid
• Psychiatric disease with possible coin ingestion ^[64]
• Alcoholism
• Exposure to lead, such as via pipes in older houses
• History of myelodysplastic syndrome
• General symptoms of anemia, including malaise, fatigue, and dyspnea on exertion

The following physical examination features are suggestive of sideroblastic anemia:

• General - Growth retardation in children
• Vital signs - Hypothermia, hypotension, tachycardia
• Eyes - Scleral icterus
• Oral - Lead line on teeth margins
• Skin - Photosensitivity (porphyria), petechiae (myelodysplastic syndrome), jaundice, bronze coloring
• Neurologic - Ataxia, diminished deep-tendon reflexes, incoordination
• Cardiovascular - Fatigue, heart failure symptoms such as shortness of breath, jugular venous distension, orthopnea, paroxysmal nocturnal dyspnea, peripheral edema
• Respiratory - Dyspnea
• Abdominal - Splenomegaly, abdominal tenderness secondary to bleeding, abdominal distension, caput medusae, spider angiomata, abdominal striae
• Musculoskeletal - Muscular weakness, arthralgias
• Genitourinary - Pink staining of diapers from porphyrins in urine, erectile dysfunction

Any complication of anemia in general, such as bleeding, high-output heart failure, significant fatigue, and weight loss, may be seen in sideroblastic anemias. See Anemia. Complications specific to sideroblastic anemia result primarily from iron overload throughout the body's organ systems, especially the liver and rarely the heart. Iron overload is a result of ineffective erythropoiesis caused by mitochondrial iron toxicity, which increases iron absorption.[65]  Thus, patients with underlying sideroblastic anemia can present with evidence of acute liver failure or cirrhosis, due to the accumulation of iron in the liver, or heart failure due to the accumulation of iron in the heart.

The workup for sideroblastic anemia may include the following:

• Complete blood count (CBC)
• Peripheral smear,
• Iron studies (eg, ferritin and total iron-binding capacity [TIBC])
• Bone marrow aspiration and biopsy
• Other studies as appropriate
• Various forms of genetic testing and genotyping

In patients with sideroblastic anemia, the CBC usually reveals anemia, mostly moderate, although severe anemia has been reported.[66] The mean corpuscular volume (MCV) is usually low, with a microcytic picture; however, normocytic, macrocytic,[67] and classic dimorphic (normocytic + microcytic)[68] smears are not uncommon.

Normochromic vs hypochromic red blood cell (RBC).

Siderocytes with Pappenheimer bodies (hypochromic erythrocytes with basophilic iron deposits) are sideroblasts that have matured enough to make it to peripheral blood.

Pappenheimer bodies seen on giemsa stain.

Dimorphic anemia is not specific for sideroblastic anemia and is also seen in combined vitamin B-12 deficiency with iron deficiency and after blood transfusions.[69] Other cell lines may be undisturbed in pure sideroblastic anemia, but in sideroblastic anemia that is associated with myelodysplastic syndrome (MDS), leukopenia, thrombocytopenia, or even thrombocytosis may be observed.

The peripheral smear may exhibit basophilic stippling in cases of lead poisoning.[70]

Basophilic stippling in lead poisoning.

Iron studies may show increased an iron level with decreased TIBC (see the image below) . A very low ferritin level strongly favors iron deficiency as the primary cause of anemia. In fact, iron deficiency may mask underlying sideroblastic anemia as hypochromic anemia, with the appearance of sideroblasts in bone marrow once the iron stores are replenished.[71] Periodic iron studies are essential even for those who are not transfusion dependent.

Serum lead, alcohol, γ-glutamyltransferase (GGT), copper, and zinc levels can be measured. Surrogates for vitamin B-6 that can be measured in plasma include pyridoxal 5′ phosphate (PLP) and 4-pyridoxic acid (4-PA).[72] 4-PA can also be measured in urine.

Magnetic resonance imaging (MRI) of the posterior cranial fossa is indicated in anemia-ataxia syndromes to rule out primary cerebellar pathology such as space-occupying lesions.

In congenital or suspected congenital anemias, determination of the exact mutation type (eg, ABC7) may provide useful information for the physician and the family members of affected patients, even if it may not affect immediate patient management. This can be accomplished by means of polymerase chain reaction (PCR) evaluation.

A urine porphyrin profile may reveal erythropoietic porphyria.

Usually, when a physician is faced with the diagnosis of sideroblastic anemia, bone marrow aspiration and biopsy has already been done. Attention should be paid to other cell lines (ie, megakaryocytes, myelocytes) because MDS is a part of the differential diagnosis (see Differentials). If iron deficiency anemia is of unclear etiology and fails to respond to iron replacement during the workup, bone marrow aspiration and biopsy should be included in the workup.

Patients initially presenting with hypochromic anemia may end up receiving iron supplements if a bone-marrow biopsy is not performed and thus develop iron overload.

It is important to obtain cytogenetic studies on the bone marrow aspirate samples, as quite often this may be the only way confirm a myelodysplastic syndrome.

In the revised WHO classification, if an SF3B1 mutation is identified, a diagnosis of MDS-RS may be made if ring sideroblasts comprise as few as 5% of nucleated erythroid cells, whereas at least 15% ring sideroblasts are required in cases lacking a demonstrable SF3B1 mutation.[4]  

The WHO criteria for MDS/MPN-RS-T include thrombocytosis (≥450 × 109/L) associated with refractory anemia, dyserythropoiesis in the bone marrow with ring sideroblasts accounting for 15% or more of erythroid precursors, and megakaryocytes with features resembling those in primary myelofibrosis (PMF) or essential thrombocythemia (ET).Unlike MDS-RS the number of ring sideroblasts required for a diagnosis of MDS/MPN-RS-T is not altered by the presence or absence of a mutation in SF3B1.[4]  

Treatment of sideroblastic anemia may include the following:

• Removal of toxic agents
• Administration of pyridoxine, thiamine, or folic acid
• Transfusion (along with antidotes if iron overload develops from transfusion)
• Other medical measures
• Bone marrow or liver transplantation

Admission and inpatient care may be needed for patients with sideroblastic anemia and cirrhosis, as well as those who have need of repeated blood transfusions. Regular follow-up is essential, even for patients with sideroblastic anemia whose condition responds to therapy.

Acute idiopathic sideroblastic anemia, refractory anemia with ring sideroblasts (RARS) or myelodysplastic syndrome (MDS) must be monitored for potential transformation into acute leukemias.

Go to Anemia, Iron Deficiency Anemia, and Chronic Anemia for complete information on these topics.

Toxic agents such as zinc, lead, and drugs such as penicillamine should be removed whenever possible; however, this may not always be easy. For example, isoniazid is the mainstay of treatment of active tuberculosis, and a risk-benefit analysis of treatment discontinuation is essential for each patient.

Pyridoxine

Pyridoxine (vitamin B-6) deserves a trial in all cases of sideroblastic anemia as many acquired and certain congenital forms of sideroblastic anemia respond to this relatively safe agent. The response will be evident in a few weeks, with reticulocytosis and improving hemoglobin levels.

The dose should be tailored to the patient’s tolerance. Dosages up to 1 g/day have been used, but the goal is to find a dosage of pyridoxine (usually 50-200 mg/d) that will maintain the hemoglobin level and yet prevent toxicity (peripheral neuropathy). For patients whose condition responds, treatment is lifelong.

Pyridoxal 5′ phosphate (PLP) is an active form of pyridoxine that has been successfully used in the treatment of sideroblastic anemias in some patients who do not respond to pyridoxine.[73]

Folic acid

Folic acid by itself has been reported to reverse sideroblastic changes in some patients.[74] It is advisable to supplement folate in pyridoxine-responsive cases to ensure an adequate supply during a period of increased hemoglobin synthesis.

Thiamine

As would be expected from its name, thiamine-responsive megaloblastic anemia is treated with thiamine. In this acquired form of sideroblastic anemia, supraphysiologic doses of thiamine (25 to 75 mg daily) have been shown to improve not only the anemia component, but also the associated diabetes and deafness.[49] However, some studies indicate that these doses may be ineffective during puberty.[75]

Transfusion is the mainstay of treatment for patients whose sideroblastic anemia does not respond to pyridoxine therapy.[76] It is problematic and should be avoided if the anemia is mild to moderate and the patient asymptomatic.

Even without transfusions, patients with sideroblastic anemia are prone to develop iron overload.[77] Transfusion in sideroblastic anemia has been known to worsen iron overload and lead to secondary hemochromatosis and cirrhosis, which can be fatal.[78]

Other agents studied for the treatment of sideroblastic anemias include the following:

• Heme arginate as an infusion has been used with mixed results. It is not a first-line drug. ^[79]
• Erythropoietin (EPO) has been tried and does not appear to reverse sideroblastic anemia ^[80] ; it has also been reported to cause neutropenia in this setting. ^[81] EPO in combination with granulocyte colony-stimulating factor (G-CSF) appears to have a better response rate than EPO alone (50%). ^{[82, 83]}
• Lenalidomide may reduce transfusion needs in some patients with refractory anemia with ring sideroblasts (RARS). ^[84]
• Prednisone and danazol have not been effective, ^[85] except for some patients with active connective tissue disease (eg, systemic lupus erythematosus (SLE), ^[86] ) in whom sideroblastic changes disappear with prednisone when the SLE flare subsides.
• Cytotoxic therapies such as cyclophosphamide have been tried with some success in patients with erythropoietin inhibitors that result in ineffective erythropoiesis. ^[87]
• Chloroquine has been successfully used to treat pyridoxine-resistant sideroblastic anemia, but no large study has been done, and thus only limited data are available. ^[88] The drug affects heme metabolism and is also used in certain porphyrias.
• Ubidecarenone (coenzyme Q10) has been used with mixed results in the treatment of sideroblastic anemia and is not recommended as a standard of care. ^{[89, 90]}
• Azacitidine and other newer agents being used for myelodysplastic syndrome (MDS) have not been specifically studied or approved for sideroblastic anemias in general.

Bone marrow transplantation is a treatment of last resort and is best saved for young patients whose conditions are pyridoxine resistant[91] and transfusion dependent[92] and who have a human leukocyte antigen (HLA)-matched sibling. Even then, the response ranges from cure to death within weeks.[62] Severe graft versus host disease has been reported even with HLA-identical sibling donors.[63] The evidence is limited to a few case reports in the literature.[93, 94, 95]

Liver transplantation has been used in cases of sideroblastic anemia with cirrhosis and iron overload that is not responsive to chelation and phlebotomy.

While surgical management is often not needed in patients with sideroblastic anemias, untreated patients can build up an excess amount of iron in their organs, in particular the liver. As noted above, this hepatic iron overload can act very similarly to congenital hemochromatosis, and eventually lead tocan build up in such excess and cause profound liver failure. At that point the only clinical management would be to go for a Liver Transplantation. 

Patients who being considered for liver transplantation will need to undergo a workup to assess their degree of illness and overall suitability for the procedure, to help determine their eligibility for listing (see Liver Transplantation). In the rare cases where iron accumulates to toxic levels in the heart, heart transplantation  may eventually be needed if all other treatments fail. 

See Anemia for more information on the general managment of anemia-related complications. For iron overload–related complications, the primary goal is to eliminate excess iron 

Management of iron overload

Deferoxamine (desferrioxamine; Desferal) can be used if iron overload develops from repeated blood transfusions.[96]  Although effective, it must be administered by a subcutaneous pump for several hours a day.

Deferasirox (Exjade) is a newer oral iron chelator that has been used instead of deferoxamine and appears to be effective. First used in Europe, it has been introduced in United States and is a once-daily pill. Renal toxicity and allergic reactions are a concern.

Phlebotomy can be performed for iron overload.[97]  In some patients who do not tolerate deferoxamine therapy, this procedure is an option, but the limiting factor may be anemia.

Refractory iron overload

In some cases, chelation or phlebotomy may be unable to prevent the accumulation of iron to toxic levels, most often in the liver and more rarely the heart. Treatment options for liver toxicity are slim; liver transplantation may eventually prove necessary. For iron accumulation in the heart, management focuses on treating heart failure secondary to restrictive cardiomyopathy. However, continuing iron buildup may eventually result in such profound heart failure that heart transplantation becomes the only option.

Transfer to the care of a hematologist is recommended, especially for cases of pyridoxine-resistant sideroblastic anemia and for patients who become transfusion dependent. Consider consultations with a neurologist for mitochondrial myopathy-anemia syndromes.

If surgical treatment is ever needed in the form of a liver or heart transplant, it is key to get hepatologists, cardiologists, and transplant surgeons all invovled in the care of the patient.

In cases of sideroblastic anemia, the goals of pharmacotherapy are to reduce morbidity and prevent complications. Medications used include vitamins and antidotes to toxic metal ions.

Class Summary

Antidotes are used to decrease toxic blood levels of metal ions such as iron.

Deferoxamine mesylate (Desferal)

Deferoxamine (desferrioxamine) is usually administered as a slow subcutaneous infusion through a portable pump. It is freely soluble in water. Approximately 8 mg of iron is bound by 100 mg of deferoxamine. Deferoxamine promotes renal and hepatic excretion in urine and bile in feces. It gives urine a red discoloration.

Deferoxamine readily chelates iron from ferritin and hemosiderin but not transferrin. It does not affect iron in cytochromes or hemoglobin. It is most effective when provided to the circulation continuously by infusion. It helps prevent damage to the liver and bone marrow from iron deposition.

Deferoxamine may be administered either by intramuscular (IM) injection or by slow intravenous (IV) infusion. It does not effectively chelate other trace metals of nutritional importance. It is provided in vials containing 500 mg of lyophilized sterile drug. Two mL of sterile water for injection should be added to each vial, bringing the concentration to 250 mg/mL. For IV use, this may be diluted in 0.9% sterile saline, 5% dextrose solution, or Ringer solution.

The IM route is the preferred route of administration, except in the presence of hypotension and cardiovascular collapse, when the IV route should be considered.

Deferasirox (Exjade)

Deferasirox is supplied as a tab for oral suspension. It is an oral iron chelation agent demonstrated to reduce liver iron concentration in adults and children who receive repeated red blood cell (RBC) transfusions. It binds iron with high affinity in a 2:1 ratio.

Deferasirox is approved for treatment of chronic iron overload due to multiple blood transfusions. Treatment initiation is recommended with evidence of chronic iron overload (ie, transfusion of about 100 mL/kg packed RBCs [about 20 U for a 40-kg person] and a serum ferritin level consistently higher than 1000 µg/L).

Class Summary

Vitamins are used to meet necessary dietary requirements and are used in metabolic pathways, as well as DNA and protein synthesis.

Folic acid

Folic acid is a water-soluble vitamin used in nucleic acid synthesis. It is required for normal erythropoiesis.

Pyridoxine (Aminoxin)

Pyridoxine is necessary for normal metabolism of proteins, carbohydrates, and fats. It is also involved in the synthesis of gamma-aminobutyric acid (GABA) within the central nervous system.

Thiamine

Specifically useful in the syndromic form of SA called Thiamine Responsive Megaloblastic Anemia, where the SLC19A2 gene which aids in the transport of Thiamine is dysfunctional. Supplementing Thiamine at high doses anywhere from 25mg - 75mg/day will help replenish the thiamine that these patients will be missing.