Sideroblastic Anemia

Etiology

The hereditary form of sideroblastic anemia is caused by mutations in genes that are involved in heme synthesis, iron-sulfur cluster biogenesis, or mitochondrial metabolism.[7][9][10] For heme synthesis, the gene defect is on the X chromosome, leading to mutations in the aminolevulinate synthase (ALAS2), adenosine triphosphate-binding cassette B7 (ABCB7) or glutaredoxin 5 (GRLX5) enzymes. Other congenital causes include mutations in the mitochondrial transporter (SLC25A38), thiamine transporter (SLC19A2), RNA modifying enzyme pseudouridine synthase (PUS1), mitochondrial tyrosyl-tRNA synthase (YARS2), and mitochondrial DNA deletions.[11] 

The most common cause of hereditary sideroblastic anemia is the X-linked type caused by a mutation of the gene-forming ALAS2 enzyme.[10] The ALAS2, SLC25A38, GLRX5, HSPA9, ABCB7 genes when mutated cause microcytic anemia while the mitochondrial genes (SLC19A2, PUS1, YARS2, TRNT1) when mutated cause macrocytic anemia.[12] In other words, the X-linked mutations cause microcytic anemia, and mitochondrial DNA deletions cause macrocytic anemia.[9]

Acquired sideroblastic anemias may arise from primary or secondary causes. Primary causes include clonal sideroblastic anemias, bone marrow stem cell disorders categorized under the broader groups of MDS and myeloproliferative neoplasms (MPN).[1] RARS is now classified under myelodysplastic syndrome with ring sideroblasts (MDS-RS), and RARS with thrombocytosis is now classified as a myelodysplastic, myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).[13][1] The morphology observed during diagnosis is critical, significantly influencing the disease's progression. 

Most cases of RARS evolve in 1 of 2 ways: either they become a type of low-risk MDS with a normal lifespan, or they progress to a higher-grade MDS or acute myeloid leukemia. Most RARS cases fall into the first category, with only 7% to 10% of patients progressing to the more severe forms. Secondary causes of sideroblastic anemia are copper deficiency (or zinc toxicity), drugs (such as isoniazid, chloramphenicol, or linezolid), and excessive alcohol use.[1][14][15] Sideroblastic anemia secondary to copper deficiency, certain medications, or excessive alcohol consumption can be completely reversed once the underlying cause is eliminated.

Epidemiology

Sideroblastic anemia is considered a rare disease.[7] By definition, rare diseases affect fewer than 200,000 people in the United States. Due to the low incidence and prevalence, researchers do not have definite statistical data on its epidemiology. The disorder affects a wide age range, from infants with congenital forms to middle-aged and older individuals.[16]

Pathophysiology

Understanding the pathophysiology of sideroblastic anemia, heme biosynthesis, and the consequences of defective enzyme/transport genes is important. The first step in heme synthesis involves the transport of glycine into the mitochondria by the SLC25A38 transporter, which combines with succinyl-coenzyme A to form aminolevulinic acid (ALA). [3] This reaction is catalyzed by the enzyme aminolevulinic acid synthase 2 (ALAS2). Once synthesized, ALA is transported from the mitochondria to the cytosol. A defect in ALAS2, which impairs ALA formation, leads to heme deficiency and the development of sideroblastic anemia. [3] Additionally, mutations in the ABCB7 and GLRX5 genes cause heme deficiency through distinct pathways, as outlined below.[2] Other gene mutations, with diverse functions, also contribute to the development of sideroblastic anemia.

Hereditary sideroblastic anemia arises from defects in genes encoding enzymes involved in heme biosynthesis, located both on autosomal chromosomes and within the mitochondria.[1] The diseases caused by these gene mutations are described as non-syndromic and syndromic. Non-syndromic disorders include X-linked sideroblastic anemia, also known as sideroblastic anemia 1 (SIDBA1), SIDBA2, SIDBA3, and SIDBA4. In contrast, syndromic diseases include X-linked sideroblastic anemia with ataxia; Pearson marrow-pancreas syndrome; thiamine-responsive megaloblastic anemia; myopathy, lactic acidosis, and sideroblastic anemia; sideroblastic anemia with immunodeficiency, fevers, and developmental delay; and NDUFB11 deficiency.[12] The list below outlines different types of sideroblastic anemia and their corresponding pathophysiology. All of these types are involved in heme synthesis either directly or indirectly.

Non-syndromic conditions include:

• SIDBA1 has been reported to be caused by various mutations, including missense, nonsense mutations, and mutations at promoter or enhancer regions.[17]
• All these mutations show an X-linked inheritance pattern. However, ALAS2 has also been reported in females due to acquired unbalanced lyonization causing heterozygous ALAS2 mutation.[12]     
• A mutation in SLC25A38 causes SIDBA2. Various mutations have been reported, including nonsense, frameshift, and missense mutations.[18] 
• As mentioned above, SLC25A38 is a mitochondrial glycine transporter that transports glycine into the mitochondria. Glycine is required to form ALA when joined with succinyl-coenzyme A. When mutated, this formation is limited, impeding the formation of heme.                     
• SIDBA3 is a result of a GLRX5 mutation. This type is rare, as only 2 affected families have been reported. This condition is caused by a homozygous mutation that interferes with the splicing of GLRX5 messenger RNA, which reduces the function of GLRX5, which produces an iron-sulfur cluster in the mitochondria.[12]
• A mutation of HSPA9, the mitochondrial chaperone protein, causes SIDBA4. As in previous types, various mutations occur, including missense, nonsense, frameshift, and in-frame deletion mutations. The absence of HSPA9 in erythroid cell lines inhibits erythroid cell differentiation.

Syndromic conditions are:

• X-linked sideroblastic anemia with ataxia (XLSA/A) is caused by a mutation in the adenosine triphosphate-binding cassette transporter (ABCB7). ABCB7 is involved in iron-sulfur cluster biogenesis, which helps transport iron to the cytosol during heme production. A missense mutation in this gene would lead to X-linked sideroblastic anemia with cerebellar ataxia.[12]                       
• Pearson marrow-pancreas syndrome is due to a deletion of mitochondria DNA. The mechanism causing sideroblastic anemia is unknown, but it was reported that the deletion of the mitochondria DNA causes a defect in the respiratory chain of the mitochondria, causing anemia.[19] This defect leads to refractory sideroblastic anemia and exocrine pancreatic insufficiency.[20] 
• Thiamine-responsive megaloblastic anemia is caused by a mutation of the SLC19A2 gene, which aids in thiamine transport. Thiamine is needed for the production of succinyl-coenzyme A. A defect in this protein will lead to megaloblastic anemia, diabetes mellitus, and deafness.[12]                 
• Myopathy, lactic acidosis, and sideroblastic anemia are due to a mutation of PUS1, which helps translate the respiratory chain in the mitochondria (eg, a missense mutation). The reason it causes sideroblastic anemia is unknown.[12]                                                                           
• Myopathy, lactic acidosis, and sideroblastic anemia are due to a mutation in the YAR2 gene, which encodes mitochondrial tyrosyl transfer RNA synthase. The mutation of this enzyme will deplete the quantity of this enzyme. The cause of sideroblastic anemia is also unknown with this type.[12]     
• Sideroblastic anemia with immunodeficiency, fevers, and developmental delay is due to a mutation of the TRNT1 gene, which encodes CCA-adding transfer RNA nucleotidyltransferase. The pathology of sideroblastic anemia is unknown.[12]                                                                     
• NDUFB11 deficiency is due to a deletion of 3 nucleotides in the NDUFB11 gene, leading to phenylalanine deletion in the NDUFB protein, causing normocytic sideroblastic anemia and lactic acidosis.[21]

Clonal hematologic disorders, including MDS/MPN variants, are a primary cause of acquired sideroblastic anemia and are classified as lower-risk MDS. These disorders are the most commonly encountered form of sideroblastic anemia in clinical practice, typically affecting individuals older than 40. The MDS/MPN variants associated explicitly with ring sideroblasts include: MDS with ring sideroblasts and single lineage dysplasia (MDS-RS-SLD), previously known as RARS; MDS with ring sideroblasts and multilineage dysplasia (MDS-RS-MLD), formerly called refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS); and MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS), previously referred to as refractory anemia with ring sideroblasts and thrombocytosis (RARS-T).[22]

Acquired missense mutations in SF3B1, which encodes a component of the messenger RNA spliceosome, are present in up to 85% of patients with the above MDS/MPN variants.[23] SF3B1 is inserted into the spliceosome by arranging a pre-splicing complex to become a type of U2 small nuclear ribonucleoprotein.[14] The function of this gene is to help join the U2 snRNP to the pre-mRNA, and it also helps in the formation of an intermolecular helix between the 5' end of the U2 and the 3' end of the U6 small nuclear RNAs.[14] The detection of SFB3B1 mutations confirms the diagnosis of an MDS/MPN variant, is associated with a more favorable clinical outcome, and helps rule out X-linked sideroblastic anemia in female patients.[24] 

Histopathology

Siderocytes on peripheral blood smear are considered highly characteristic of sideroblastic anemia. These are hypochromic red blood cells with prominent coarse basophilic granules visible on the Wright-Giemsa stain. The granules consist of residual iron-laden mitochondria and are known as Pappenheimer bodies. Siderocytes are the mature red blood cell equivalent of the ring sideroblasts observed in the bone marrow.[25]

If a bone marrow assay is ordered for worsening anemia or progressively low neutrophil counts, it often reveals a hypocellular picture with dysplastic changes or even erythroid hyperplasia.[26] Prussian blue staining of the bone marrow aspirate smear will show the typical ring sideroblasts when viewed under the microscope (see Image. Ring Sideroblasts). This Prussian blue staining is called the Perls reaction, and there should be a minimum of 5 granules surrounding one-third of the nuclear diameter.[14] Granulopoiesis is often left-shifted, but full maturation still occurs. Bone marrow is often stained for iron and will show numerous iron-laden macrophages, which are not appreciated as well on the smear. Dyserythropoietic features, including a left shift in erythroid precursors, megaloblastoid changes, and binuclearity, are frequently observed in MDS variants but are less common in other types of sideroblastic anemia.[27] Vacuolization of erythroid and myeloid precursors is also commonly seen in copper deficiency, and there may be hyperplasia of lymphoid precursor cells.[28] 

History and Physical

The presentation of patients with sideroblastic anemia includes the common symptoms of anemia, such as fatigue, malaise, shortness of breath, palpitations, and headache. Clinicians must review all potential social exposures, alcohol use, work-related exposures, and previous surgical procedures. A history of gastrointestinal surgery, enteral or parenteral nutrition without copper supplementation, or excessive zinc intake may suggest copper deficiency. Evaluating for any past medical history of cancer, familial hematologic malignancies, and other iatrogenic causes is also essential. 

This condition requires a thorough physical examination of the patient, including a head-to-toe examination of mucous membranes, a conjunctivae examination for pallor, a cardiopulmonary examination, an evaluation of fingers for changes in nail beds secondary to anemia, and an evaluation for alternative causes of anemia. Physical examination may reveal conjunctival pallor, pale skin, and tachycardia. Some affected individuals may have bronze-colored skin due to iron overload. In some cases, especially with severe chronic forms or in associated MDS, mild hepatosplenomegaly may be present due to extramedullary hematopoiesis. Patients with syndromic hereditary sideroblastic anemia may present with uncontrolled diabetes and deafness, such as the thiamine-responsive megaloblastic anemia type. Hereditary types will be seen in younger patients with a family history, while acquired sideroblastic anemia typically occurs in older patients with possible myelodysplastic syndrome.

Evaluation

Sideroblastic anemia is primarily a laboratory diagnosis. A complete blood panel with differential chemistries and an evaluation of vitamin and mineral deficiencies (B12, folate, and copper) are necessary. The mean corpuscular volume (MCV) is a useful parameter for differentiating among types of sideroblastic anemia. The anemia is typically microcytic (low MCV) in most congenital subtypes, and nearly all acquired forms—including MDS, copper deficiency, and most medication-induced cases—tend to be normocytic or macrocytic (normal to high MCV).[25][29]

Iron studies should be conducted to assess the extent of iron overload, which will help determine the necessity for phlebotomy or iron chelation therapy and ongoing monitoring. In individuals with lab-confirmed iron overload, the severity of iron accumulation in tissues is most accurately evaluated through magnetic resonance imaging or liver biopsy. Ring sideroblasts diagnose sideroblastic anemia in the bone marrow. The red blood cells in the peripheral blood smear that contain these iron inclusions are called siderocytes.[2] 

When ring sideroblasts are confirmed using the Perls reaction, the patient's bone marrow should be checked for dysplasia and SF3B1 mutations; if present, the patient most likely has a clonal hematologic disorder such as MDS/MPN variants. If absent, the patient either has congenital or secondary acquired sideroblastic anemia. [2] Genetic testing should also be considered if secondary acquired sideroblastic anemia has been ruled out and the cause of the sideroblastic anemia is unknown.

Treatment / Management

Managing sideroblastic anemia depends on its severity. Patients with a mild or asymptomatic presentation can follow up in the outpatient clinic. Oral pyridoxine 50 to 100 mg/day has been proven to partially or completely correct anemia for patients diagnosed with X-linked sideroblastic anemia.[2] Luspatercept, a drug that promotes erythroid maturation, could be beneficial in treating congenital sideroblastic anemias characterized by significantly ineffective erythropoiesis.[30][31] Thiamine is used to treat thiamine-responsive megaloblastic anemia.(B3)

For patients who are not responsive to pyridoxine, blood transfusion is indicated if they have severe anemia.[2] Iron chelation must be considered for patients who require chronic transfusion to avoid iron overload. Starting deferoxamine or oral chelators when serum ferritin is more than 1000 ng/L is recommended.[32] Iron overload, if left untreated, can result in unresponsiveness of pyridoxine. Therefore, it is also recommended that patients with normal hemoglobin levels after pyridoxine should have phlebotomy as a treatment for iron overload.[32] Iron overload treatment is critical as studies have shown an improvement in anemia due to low iron levels and better responsiveness to pyridoxine.[32][33](A1)

Diabetes can develop in patients with syndromic congenital sideroblastic anemia, and tight glycemic control should be encouraged in such patients. Hypoglycemia should also be addressed if blood sugar is not well controlled. For secondary acquired sideroblastic anemia caused by known drugs or toxins, such drugs should be discontinued and avoided. Since it is acquired, the patient’s anemia will improve after the removal of the drug. For isoniazid, the anemia can also be reversed by administering large doses of pyridoxine. Copper should be replenished in a patient with a copper deficiency through dietary intake.

Symptomatic sideroblastic anemia in MDS/MPN variants is treated similarly to low-risk MDS. Therapies previously used include erythropoiesis-stimulating agents, granulocyte colony-stimulating factor (G-CSF), and hypomethylating agents (HMAs) such as azacytidine and decitabine, all of which are potential options to reduce the need for red blood cell transfusions.[34] Though some patients may be successful on the watch-and-wait regimen, HMAs are frequently used after the failure of conservative management with erythropoiesis-stimulating agents and G-CSF. Administration of 75 mg/m² azacitidine for 7 consecutive days with a 28-day cycle subcutaneously or intravenously is an option for patients older than 20 who meet the criteria for RARS and whose neutrophil counts are less than 1x10⁹/L.

Emerging treatments include luspatercept, an agent that stimulates late-stage erythropoiesis.[35] In the randomized, double-blind MEDALIST trial, luspatercept significantly reduced the need for red blood cell transfusions and improved hematologic outcomes in transfusion-dependent patients with low-risk MDS with ring sideroblasts.[36] Luspatercept can be used as a first-line treatment or after trying an erythropoiesis-stimulating agent.

Another newer treatment option is imetelstat, a telomerase inhibitor that showed promising results in the phase 3 IMerge trial and was approved in 2024 for transfusion-dependent low to intermediate-risk MDS. This can be used in patients who are refractory to erythropoiesis-stimulating agents.[37] For patients with MDS/MPN-RS-T, aspirin therapy is recommended if the patient has an additional JAK2V617F mutation due to an increased risk of thrombosis.[14] Often, the underlying causes of the sideroblastic anemia require therapeutic action before any condition improvement ensues.[38](A1)

Differential Diagnosis

The differential diagnosis of sideroblastic anemia includes non-clonal and clonal disorders and other more common causes of anemia.

Non-clonal disorders include: 

• Congenital conditions comprising nonsyndromic and syndromic diseases
• Secondary acquired conditions, such as copper deficiency, zinc overload, lead poisoning, and isoniazid use.

Clonal disorders include conditions include:

• Myelodysplastic syndromes with ring sideroblasts 
• Myelodysplastic syndromes with ring sideroblasts, with single lineage dysplasia 
• Myelodysplastic syndromes with ring sideroblasts, with multilineage dysplasia 
• Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.[14] 

Other more common causes of anemia which should be considered in the differential diagnosis are:

• Iron deficiency anemia
• Thalassemia
• Anemia of chronic disease
• Lead poisoning
• Blood loss.

Prognosis

The prognosis for patients with sideroblastic anemia differs depending on the underlying cause. In secondary acquired sideroblastic anemia, the prognosis is generally favorable once the causative drugs or toxins are discontinued. In X-linked sideroblastic anemia, appropriate pyridoxine supplementation and management of iron overload can significantly improve outcomes. However, the prognosis may be poor if these conditions are not adequately addressed.

The prognosis of acquired sideroblastic anemia due to MDS/MPN variants varies depending on the underlying genetic and clinical characteristics. These disorders are typically seen in older adults and often involve mutations in the SF3B1 gene, associated with favorable outcomes.[23] However, the prognosis remains influenced by the presence of other co-occurring mutations and the risk of progression to acute myeloid leukemia. The level of blast counts and response to potential treatments will often determine the overall survival of these patients.[39] 

Complications

Sideroblastic anemia caused by mutations in XLSA, GLRX5, and SLC25A38 has been reported to cause heaptic and systemic iron overload.[2] Iron concentrates in the liver and can eventually lead to fibrosis and cirrhosis, just like in hereditary hemochromatosis. In rare situations, patients may also experience hepatomegaly, cardiomyopathy, and endocrine dysfunction, particularly when iron accumulation becomes excessive over time.[2]

Acquired sideroblastic anemia due to MDS/MPN variants is linked with severe anemia, which can cause fatigue, weakness, and exercise intolerance. Leukopenia can result in frequent infection, and thrombocytopenia can lead to easy bruising and bleeding. Additionally, there is an increased risk of transforming into acute myeloid leukemia, especially in cases with high-risk mutations. Vascular and thrombotic complications are also very prevalent in these patients.[40]