Sideroblastic Anemia

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Continuing Education Activity

Sideroblastic anemia is characterized by impaired iron utilization during erythropoiesis, leading to ring sideroblasts in the bone marrow. These ring sideroblasts are erythroid precursors with iron-laden mitochondria encircling the nucleus. The condition can be hereditary or acquired, with hereditary forms presenting as either microcytic or macrocytic anemia, depending on the specific genetic mutation and its effect on red blood cell maturation and hemoglobin synthesis. Sideroblastic anemia is associated with normal to elevated iron levels, unlike iron deficiency anemia. A notable subtype, refractory anemia with ring sideroblasts (RARS), falls under the myelodysplastic syndrome (MDS) spectrum and is characterized by significant ring sideroblasts and resistance to standard anemia treatments. Although RARS often follows an indolent course with isolated anemia, some cases may progress to more severe forms of MDS or acute myeloid leukemia.

This course provides healthcare professionals with a comprehensive understanding of the pathophysiology, diagnostic criteria, and treatment advancements in sideroblastic anemia and RARS. Participants learn to identify key genetic mutations, analyze bone marrow morphology, and assess iron metabolism’s role in disease progression. Emphasizing a multidisciplinary approach, the course highlights the collaborative efforts of hematologists, nutritionists, primary care clinicians, and mental health professionals in delivering holistic, patient-centered care. This interprofessional collaboration improves diagnostic accuracy, enhances personalized treatment plans, and addresses patients' broader nutritional, psychological, and hematologic needs, ultimately leading to better clinical outcomes and quality of life.

Objectives:

  • Identify the clinical and laboratory features of sideroblastic anemia and refractory anemia with ring sideroblasts, including ring sideroblasts and abnormal iron metabolism.

  • Evaluate and differentiate sideroblastic and refractory anemia with ring sideroblasts from other types of anemia, particularly iron deficiency anemia, by assessing iron levels, red blood cell morphology, and other laboratory findings.

  • Differentiate between sideroblastic anemia, iron deficiency anemia, and other microcytic or normochromic anemias based on iron levels, red blood cell morphology, and genetic markers.

  • Collaborate with an interprofessional team, including hematologists, genetic counselors, dietitians, and primary care providers, to deliver comprehensive care for patients with sideroblastic anemia.

Introduction

Sideroblastic anemia is a rare type that results from abnormal utilization of iron during erythropoiesis. There are different forms of sideroblastic anemia, and all forms are defined by the presence of ring sideroblasts in the bone marrow. Ring sideroblasts are erythroid precursors containing deposits of non-heme iron in mitochondria, forming a ring-like distribution around the nucleus.[1] The iron-formed ring covers at least one-third of the nucleus rim (see Images. Sideroblastic Anemia and Ringed Sideroblasts).[2] 

The hemoglobin molecule contains a crucial prosthetic group called heme, integral to its oxygen-carrying function. Structurally, heme consists of a porphyrin ring formed by 4 pyrrole rings connected by methine bridges at the alpha positions, with a central iron atom coordinated within the ring.[3] This iron center enables hemoglobin to bind and transport oxygen efficiently to tissues throughout the body. Other functions of heme apart from the formation of hemoglobin include gas sensing, signal transduction, biological clock, circadian rhythm, and microRNA processing.[4]

Sideroblastic anemia results from abnormal erythropoiesis during heme production. Eighty-five percent of heme is produced in the cytoplasm and mitochondria of the erythroblast cells, while the remainder is produced in hepatocytes.[3] In the Shemin pathway, also known as the heme biosynthesis pathway, 8 enzymes catalyze sequential reactions for heme synthesis. These enzymes include aminolevulinic acid synthase, porphobilinogen synthase, porphobilinogen deaminase, uroporphyrinogen III synthase, uroporphyrinogen decarboxylase, coproporphyrinogen oxidase, protoporphyrinogen oxidase, and ferrochelatase.[3] 

There are 2 forms of sideroblastic anemia: hereditary and acquired. Hereditary sideroblastic anemia primarily causes microcytic anemia due to defective heme synthesis, but certain mutations can lead to normocytic or, in rare cases, macrocytic anemia.[5] Unlike iron deficiency anemia, where there is a depletion of iron stores, patients with sideroblastic anemia have normal or high iron levels. Other microcytic anemias include thalassemia and anemia of chronic disease.[6]

Refractory anemia with ring sideroblasts (RARS) is an acquired form of sideroblastic anemia that is classified as a type of myelodysplastic syndrome (MDS), which is characterized by anemia and the presence of 15% or more ring sideroblasts in the marrow. Generally, the patient presents with normochromic, normocytic anemia with overall erythroid hyperplasia as the body attempts to compensate for ineffective erythropoiesis.[7][8] The hemoglobin level is generally 9 to 12 g/dL, though lower levels may be present. The red blood cells may show dimorphism (with both hypochromic and normochromic populations) and variable degrees of dyserythropoietic and occasional megaloblastic features. Granulopoiesis and megakaryocytopoiesis are normal. Platelet and neutrophil counts can vary but are typically normal or mildly increased.

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.

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]

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]

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]

Deterrence and Patient Education

Deterrence and patient education are critical components in managing patients with sideroblastic anemia. Educating patients and caregivers about the disease, including its triggers and complications, is essential for effective prevention and management. Clinicians should stress the necessity of avoiding drugs that can induce sideroblastic anemia. Patients should be informed about the importance of avoiding substances that can exacerbate the condition, such as alcohol, lead, and certain medications like isoniazid, which can contribute to the development of sideroblastic anemia.[14] 

Additionally, those with iron overload must understand the need to limit their intake of iron-rich foods, particularly red meat, to prevent further complications. Regular follow-up with clinicians, adherence to prescribed treatments like pyridoxine and iron chelators, and maintaining a balanced diet rich in essential vitamins and minerals are all vital for improving patient outcomes. More clinical research is needed to better understand these diseases' prognosis and epidemiology. Through comprehensive education and proactive management strategies, patients can better manage their condition and reduce the risk of severe complications associated with sideroblastic anemia.

Enhancing Healthcare Team Outcomes

Sideroblastic anemia and RARS are rare diseases. When patients are seen in primary care clinics with anemia, most are assumed to have iron deficiency anemia, which is significantly more common. However, clinicians must consider the possibility of less common differentials, such as sideroblastic anemia and RARS, in the appropriate clinical scenario. Primary care physicians, advanced clinicians, and internists are responsible for recognizing these diseases early for proper patient treatment and best outcomes. 

Patients who develop RARS may be at risk for subsequent progression to acute myeloid leukemia. Therefore, communication between the pathologist and hematologist/primary care physician is essential. Once a case of RARS is considered in the differential diagnosis, a careful evaluation of the peripheral smear with iron staining performed is in order, as well as ancillary analysis for SF3B1 mutations. Treatment will often be determined by the clinician shortly after the review of the peripheral blood smear.[26]

Patients with sideroblastic anemia and RARS benefit significantly from an interprofessional team, as this collaborative approach ensures comprehensive care. Patients with sideroblastic anemia require the expertise of diverse healthcare professionals, including hematologists, pathologists, primary care clinicians, advanced clinicians, pharmacists, nutritionists, genetic counselors, and mental health specialists. Hematologists and pathologists provide specialized knowledge for diagnosing and treating patients with anemia, while primary care and advanced clinicians coordinate overall patient care and monitor for associated conditions.

Pharmacists play a key role in managing medications and monitoring for adverse events. Nutritionists can address dietary deficiencies that may exacerbate symptoms, and genetic counselors offer insights into hereditary aspects of the disease. Mental health specialists support patients in coping with the emotional and psychological impacts of chronic illness. The collaboration among the interprofessional healthcare team ensures a holistic approach to patient care, addressing not only the direct effects of these diseases but also the broader health and well-being of the patient. This integrated approach improves care management, enhances patient quality of life, and can potentially slow disease progression.



(Click Image to Enlarge)
<p>Sideroblastic Anemia

Sideroblastic Anemia. There are different forms of sideroblastic anemia, and all forms are defined by the presence of ring sideroblasts in the bone marrow, shown in the image.

Contributed by S Bhimji, MD


(Click Image to Enlarge)
<p>Ring Sideroblasts

Ring Sideroblasts. Abnormal deposition of iron in the mitochondria of red cell precursors forming a ring around the nucleus.

Paulo Henrique Orlandi Mourao, Pubic Domain, via Wikimedia Commons


(Click Image to Enlarge)
<p>Ringed Sideroblasts. This image shows ringed sideroblasts in dark pink.</p>

Ringed Sideroblasts. This image shows ringed sideroblasts in dark pink.

Contributed by S Bhimji, MD

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References


[1]

Sheftel AD, Richardson DR, Prchal J, Ponka P. Mitochondrial iron metabolism and sideroblastic anemia. Acta haematologica. 2009:122(2-3):120-33. doi: 10.1159/000243796. Epub 2009 Nov 10     [PubMed PMID: 19907149]


[2]

Camaschella C. Hereditary sideroblastic anemias: pathophysiology, diagnosis, and treatment. Seminars in hematology. 2009 Oct:46(4):371-7. doi: 10.1053/j.seminhematol.2009.07.001. Epub     [PubMed PMID: 19786205]


[3]

Severance S, Hamza I. Trafficking of heme and porphyrins in metazoa. Chemical reviews. 2009 Oct:109(10):4596-616. doi: 10.1021/cr9001116. Epub     [PubMed PMID: 19764719]


[4]

Sun F, Cheng Y, Chen C. Regulation of heme biosynthesis and transport in metazoa. Science China. Life sciences. 2015 Aug:58(8):757-64. doi: 10.1007/s11427-015-4885-5. Epub 2015 Jun 22     [PubMed PMID: 26100009]


[5]

Fitzsimons EJ, May A. The molecular basis of the sideroblastic anemias. Current opinion in hematology. 1996 Mar:3(2):167-72     [PubMed PMID: 9372069]

Level 3 (low-level) evidence

[6]

Massey AC. Microcytic anemia. Differential diagnosis and management of iron deficiency anemia. The Medical clinics of North America. 1992 May:76(3):549-66     [PubMed PMID: 1578956]


[7]

Brissot P, Bernard DG, Brissot E, Loréal O, Troadec MB. Rare anemias due to genetic iron metabolism defects. Mutation research. Reviews in mutation research. 2018 Jul-Sep:777():52-63. doi: 10.1016/j.mrrev.2018.06.003. Epub 2018 Jun 22     [PubMed PMID: 30115430]


[8]

Brattås MKL, Reikvam H. [Ring sideroblasts]. Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke. 2017 Nov 14:137(21):. doi: 10.4045/tidsskr.17.0502. Epub 2017 Nov 13     [PubMed PMID: 29135187]


[9]

Li B, Wang JY, Liu JQ, Shi ZX, Peng SL, Huang HJ, Qin TJ, Xu ZF, Zhang Y, Fang LW, Zhang HL, Hu NB, Pan LJ, Qu SQ, Xiao ZJ. [Gene mutations from 511 myelodysplastic syndromes patients performed by targeted gene sequencing]. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi. 2017 Dec 14:38(12):1012-1016. doi: 10.3760/cma.j.issn.0253-2727.2017.12.002. Epub     [PubMed PMID: 29365392]

Level 2 (mid-level) evidence

[10]

Harigae H. [Biology of sideroblastic anemia]. [Rinsho ketsueki] The Japanese journal of clinical hematology. 2017:58(4):347-352. doi: 10.11406/rinketsu.58.347. Epub     [PubMed PMID: 28484165]


[11]

Fujiwara T, Harigae H. Pathophysiology and genetic mutations in congenital sideroblastic anemia. Pediatrics international : official journal of the Japan Pediatric Society. 2013 Dec:55(6):675-9. doi: 10.1111/ped.12217. Epub     [PubMed PMID: 24003969]


[12]

Furuyama K, Kaneko K. Iron metabolism in erythroid cells and patients with congenital sideroblastic anemia. International journal of hematology. 2018 Jan:107(1):44-54. doi: 10.1007/s12185-017-2368-0. Epub 2017 Nov 14     [PubMed PMID: 29139060]


[13]

Patnaik MM, Tefferi A. Refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis: "2019 Update on Diagnosis, Risk-stratification, and Management". American journal of hematology. 2019 Apr:94(4):475-488. doi: 10.1002/ajh.25397. Epub 2019 Jan 24     [PubMed PMID: 30618061]


[14]

Patnaik MM, Tefferi A. Refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis (RARS-T): 2017 update on diagnosis, risk-stratification, and management. American journal of hematology. 2017 Mar:92(3):297-310. doi: 10.1002/ajh.24637. Epub     [PubMed PMID: 28188970]


[15]

Liapis K, Vrachiolias G, Spanoudakis E, Kotsianidis I. Vacuolation of early erythroblasts with ring sideroblasts: a clue to the diagnosis of linezolid toxicity. British journal of haematology. 2020 Sep:190(6):809. doi: 10.1111/bjh.16795. Epub 2020 Jun 8     [PubMed PMID: 32510577]


[16]

Ducamp S, Fleming MD. The molecular genetics of sideroblastic anemia. Blood. 2019 Jan 3:133(1):59-69. doi: 10.1182/blood-2018-08-815951. Epub 2018 Nov 6     [PubMed PMID: 30401706]


[17]

Harigae H, Furuyama K. Hereditary sideroblastic anemia: pathophysiology and gene mutations. International journal of hematology. 2010 Oct:92(3):425-31. doi: 10.1007/s12185-010-0688-4. Epub 2010 Sep 17     [PubMed PMID: 20848343]


[18]

Guernsey DL, Jiang H, Campagna DR, Evans SC, Ferguson M, Kellogg MD, Lachance M, Matsuoka M, Nightingale M, Rideout A, Saint-Amant L, Schmidt PJ, Orr A, Bottomley SS, Fleming MD, Ludman M, Dyack S, Fernandez CV, Samuels ME. Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia. Nature genetics. 2009 Jun:41(6):651-3. doi: 10.1038/ng.359. Epub 2009 May 3     [PubMed PMID: 19412178]


[19]

Smith OP, Hann IM, Woodward CE, Brockington M. Pearson's marrow/pancreas syndrome: haematological features associated with deletion and duplication of mitochondrial DNA. British journal of haematology. 1995 Jun:90(2):469-72     [PubMed PMID: 7794775]


[20]

Pearson HA, Lobel JS, Kocoshis SA, Naiman JL, Windmiller J, Lammi AT, Hoffman R, Marsh JC. A new syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction. The Journal of pediatrics. 1979 Dec:95(6):976-84     [PubMed PMID: 501502]


[21]

Torraco A, Bianchi M, Verrigni D, Gelmetti V, Riley L, Niceta M, Martinelli D, Montanari A, Guo Y, Rizza T, Diodato D, Di Nottia M, Lucarelli B, Sorrentino F, Piemonte F, Francisci S, Tartaglia M, Valente EM, Dionisi-Vici C, Christodoulou J, Bertini E, Carrozzo R. A novel mutation in NDUFB11 unveils a new clinical phenotype associated with lactic acidosis and sideroblastic anemia. Clinical genetics. 2017 Mar:91(3):441-447. doi: 10.1111/cge.12790. Epub 2016 May 25     [PubMed PMID: 27102574]


[22]

Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19:127(20):2391-405. doi: 10.1182/blood-2016-03-643544. Epub 2016 Apr 11     [PubMed PMID: 27069254]


[23]

Malcovati L, Karimi M, Papaemmanuil E, Ambaglio I, Jädersten M, Jansson M, Elena C, Gallì A, Walldin G, Della Porta MG, Raaschou-Jensen K, Travaglino E, Kallenbach K, Pietra D, Ljungström V, Conte S, Boveri E, Invernizzi R, Rosenquist R, Campbell PJ, Cazzola M, Hellström Lindberg E. SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts. Blood. 2015 Jul 9:126(2):233-41. doi: 10.1182/blood-2015-03-633537. Epub 2015 May 8     [PubMed PMID: 25957392]


[24]

Broséus J, Alpermann T, Wulfert M, Florensa Brichs L, Jeromin S, Lippert E, Rozman M, Lifermann F, Grossmann V, Haferlach T, Germing U, Luño E, Girodon F, Schnittger S, MPN and MPNr-EuroNet (COST Action BM0902). Age, JAK2(V617F) and SF3B1 mutations are the main predicting factors for survival in refractory anaemia with ring sideroblasts and marked thrombocytosis. Leukemia. 2013 Sep:27(9):1826-31. doi: 10.1038/leu.2013.120. Epub 2013 Apr 18     [PubMed PMID: 23594705]


[25]

Rodriguez-Sevilla JJ, Calvo X, Arenillas L. Causes and Pathophysiology of Acquired Sideroblastic Anemia. Genes. 2022 Aug 30:13(9):. doi: 10.3390/genes13091562. Epub 2022 Aug 30     [PubMed PMID: 36140729]


[26]

Gill H, Choi WW, Kwong YL. Refractory anemia with ringed sideroblasts: more than meets the eye. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010 Nov 10:28(32):e654-5. doi: 10.1200/JCO.2010.29.5220. Epub 2010 Aug 16     [PubMed PMID: 20713854]


[27]

Lefèvre C, Bondu S, Le Goff S, Kosmider O, Fontenay M. Dyserythropoiesis of myelodysplastic syndromes. Current opinion in hematology. 2017 May:24(3):191-197. doi: 10.1097/MOH.0000000000000325. Epub     [PubMed PMID: 28072603]

Level 3 (low-level) evidence

[28]

Pirruccello E, Luu HS, Chen W. Haematogone hyperplasia in copper deficiency. British journal of haematology. 2016 May:173(3):335. doi: 10.1111/bjh.13964. Epub 2016 Mar 7     [PubMed PMID: 26947425]


[29]

Maner BS, Killeen RB, Moosavi L. Mean Corpuscular Volume. StatPearls. 2025 Jan:():     [PubMed PMID: 31424859]


[30]

Van Dijck R, Goncalves Silva AM, Rijneveld AW. Luspatercept as Potential Treatment for Congenital Sideroblastic Anemia. The New England journal of medicine. 2023 Apr 13:388(15):1435-1436. doi: 10.1056/NEJMc2216213. Epub     [PubMed PMID: 37043658]


[31]

Shao Y, He L, Ding S, Fu R. Luspatercept for the treatment of congenital sideroblastic anemia: Two case reports. Current research in translational medicine. 2024 Mar:72(1):103438. doi: 10.1016/j.retram.2024.103438. Epub 2024 Jan 12     [PubMed PMID: 38244303]

Level 3 (low-level) evidence

[32]

Angelucci E, Barosi G, Camaschella C, Cappellini MD, Cazzola M, Galanello R, Marchetti M, Piga A, Tura S. Italian Society of Hematology practice guidelines for the management of iron overload in thalassemia major and related disorders. Haematologica. 2008 May:93(5):741-52. doi: 10.3324/haematol.12413. Epub 2008 Apr 15     [PubMed PMID: 18413891]

Level 1 (high-level) evidence

[33]

Cotter PD, May A, Li L, Al-Sabah AI, Fitzsimons EJ, Cazzola M, Bishop DF. Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing X-linked sideroblastic anemia: increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis. Blood. 1999 Mar 1:93(5):1757-69     [PubMed PMID: 10029606]


[34]

Greenberg PL, Stone RM, Al-Kali A, Bennett JM, Borate U, Brunner AM, Chai-Ho W, Curtin P, de Castro CM, Deeg HJ, DeZern AE, Dinner S, Foucar C, Gaensler K, Garcia-Manero G, Griffiths EA, Head D, Jonas BA, Keel S, Madanat Y, Maness LJ, Mangan J, McCurdy S, McMahon C, Patel B, Reddy VV, Sallman DA, Shallis R, Shami PJ, Thota S, Varshavsky-Yanovsky AN, Westervelt P, Hollinger E, Shead DA, Hochstetler C. NCCN Guidelines® Insights: Myelodysplastic Syndromes, Version 3.2022. Journal of the National Comprehensive Cancer Network : JNCCN. 2022 Feb:20(2):106-117. doi: 10.6004/jnccn.2022.0009. Epub     [PubMed PMID: 35130502]


[35]

Lanino L, Restuccia F, Perego A, Ubezio M, Fattizzo B, Riva M, Consagra A, Musto P, Cilloni D, Oliva EN, Palmieri R, Poloni A, Califano C, Capodanno I, Itri F, Elena C, Fozza C, Pane F, Pelizzari AM, Breccia M, Di Bassiano F, Crisà E, Ferrero D, Giai V, Barraco D, Vaccarino A, Griguolo D, Minetto P, Quintini M, Paolini S, Sanpaolo G, Sessa M, Bocchia M, Di Renzo N, Diral E, Leuzzi L, Genua A, Guarini A, Molteni A, Nicolino B, Occhini U, Rivoli G, Bono R, Calvisi A, Castelli A, Di Bona E, Di Veroli A, Ferrara F, Fianchi L, Galimberti S, Grimaldi D, Marchetti M, Norata M, Frigeni M, Sancetta R, Selleri C, Tanasi I, Tosi P, Turrini M, Giordano L, Finelli C, Pasini P, Naldi I, Santini V, Della Porta MG, Fondazione Italiana Sindromi Mielodisplastiche (FISiM) Clinical network (https://www.fisimematologia.it/). Real-world efficacy and safety of luspatercept and predictive factors of response in patients with lower risk myelodysplastic syndromes with ring sideroblasts. American journal of hematology. 2023 Aug:98(8):E204-E208. doi: 10.1002/ajh.26960. Epub 2023 May 24     [PubMed PMID: 37222267]


[36]

Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, Buckstein R, Santini V, Díez-Campelo M, Finelli C, Cazzola M, Ilhan O, Sekeres MA, Falantes JF, Arrizabalaga B, Salvi F, Giai V, Vyas P, Bowen D, Selleslag D, DeZern AE, Jurcic JG, Germing U, Götze KS, Quesnel B, Beyne-Rauzy O, Cluzeau T, Voso MT, Mazure D, Vellenga E, Greenberg PL, Hellström-Lindberg E, Zeidan AM, Adès L, Verma A, Savona MR, Laadem A, Benzohra A, Zhang J, Rampersad A, Dunshee DR, Linde PG, Sherman ML, Komrokji RS, List AF. Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes. The New England journal of medicine. 2020 Jan 9:382(2):140-151. doi: 10.1056/NEJMoa1908892. Epub     [PubMed PMID: 31914241]


[37]

Platzbecker U, Santini V, Fenaux P, Sekeres MA, Savona MR, Madanat YF, Díez-Campelo M, Valcárcel D, Illmer T, Jonášová A, Bělohlávková P, Sherman LJ, Berry T, Dougherty S, Shah S, Xia Q, Sun L, Wan Y, Huang F, Ikin A, Navada S, Feller F, Komrokji RS, Zeidan AM. Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (London, England). 2024 Jan 20:403(10423):249-260. doi: 10.1016/S0140-6736(23)01724-5. Epub 2023 Dec 1     [PubMed PMID: 38048786]

Level 1 (high-level) evidence

[38]

Morita Y, Maeda Y, Yamaguchi T, Urase F, Kawata S, Hanamoto H, Tsubaki K, Ishikawa J, Shibayama H, Matsumura I, Matsuda M. Five-day regimen of azacitidine for lower-risk myelodysplastic syndromes (refractory anemia or refractory anemia with ringed sideroblasts): A prospective single-arm phase 2 trial. Cancer science. 2018 Oct:109(10):3209-3215. doi: 10.1111/cas.13739. Epub 2018 Aug 26     [PubMed PMID: 30007103]


[39]

Lyons RM, Cosgriff TM, Modi SS, Gersh RH, Hainsworth JD, Cohn AL, McIntyre HJ, Fernando IJ, Backstrom JT, Beach CL. Hematologic response to three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009 Apr 10:27(11):1850-6. doi: 10.1200/JCO.2008.17.1058. Epub 2009 Mar 2     [PubMed PMID: 19255328]


[40]

Patnaik MM, Lasho TL, Finke CM, Hanson CA, King RL, Ketterling RP, Gangat N, Tefferi A. Vascular events and risk factors for thrombosis in refractory anemia with ring sideroblasts and thrombocytosis. Leukemia. 2016 Nov:30(11):2273-2275. doi: 10.1038/leu.2016.216. Epub 2016 Aug 1     [PubMed PMID: 27479179]