BASICS
DESCRIPTION
- Sideroblastic anemia (SA) is a disorder of iron utilization in the erythroblast resulting in ineffective erythropoiesis and variable systemic iron overload leading to anemia. It is characterized by the presence of ringed sideroblasts in the bone marrow.
- This disease process can be congenital or acquired.
- Although the body has available iron stores, iron cannot be incorporated into the hemoglobin, resulting in granules of iron that accumulate in the mitochondria where heme is produced.
EPIDEMIOLOGY
- SAs are uncommon. Incidence and prevalence are not well studied.
- Acquired forms are more common than hereditary forms and usually occur in older adults; present in 25-30% of alcoholics with anemia, most commonly with folate and vitamin B6 deficiency
- Hereditary forms vary in severity, usually manifesting in childhood.
ETIOLOGY AND PATHOPHYSIOLOGY
- Inability to use iron for the production of hemoglobin due to inherited or acquired impairment
- Ineffective erythropoiesis despite abundance of iron in the body
- Increased GI absorption of iron leading to iron overload
- Inability to use iron for heme synthesis results in sideroblasts, which are abnormal erythroblasts with granules of iron accumulated in the mitochondria, forming a ring around the nucleus.
- Congenital SAs are inherited forms of SA resulting from genetic defects:
- X-linked SA is caused by mutation in 5-aminolevulinate synthase, the first enzyme in the heme biosynthesis pathway. This is the most common congenital form. It is more prevalent in males.
- X-linked SA with spinocerebellar ataxia results from defect in ABCB7 gene.
- Mitochondrial defects:
- Defect of mitochondrial transporter SLC25A38; usually autosomal recessive
- Deficiency in mitochondrial GXRL5, which effects iron-sulfur cluster synthesis
- Deficiency of ferrochelatase, a necessary enzyme in the heme biosynthesis pathway
- Roger syndrome results from defect in thiamine transporter protein; usually improved with administration of thiamine
- Pearson syndrome results from defect in mitochondria of erythroblasts.
- Refractory anemia with ring sideroblasts (RARS) and pure SA (PSA) are subtypes of the myelodysplastic syndromes related to clonal over proliferation of hematopoietic cell lines:
- RARS is more commonly associated with acute leukemia than is PSA.
- Acquired SA is usually reversible when the inciting factor is removed. Acquired SA is more common than congenital SA and can be caused by the following:
- Alcohol
- Isoniazid
- Pyrazinamide
- Chloramphenicol
- Cycloserine
- Azathioprine
- D-penicillamine
- Linezolid (1)
- Lead poisoning
- Zinc toxicity leading to copper
- Copper deficiency
- Pyridoxine deficiency
- Zinc deficiency (2)
- Hypothermia affecting mitochondrial functions
Genetics
- Congenital form can arise from multiple gene defects:
- Defect in aminolevulinic acid synthase (ALAS-2 mutation): the first and rate-limiting enzyme in heme biosynthesis
- Defect in mitochondrial amino acid transporter (SLC25A38) (3)
- Defect in ferrochelatase
- Defect in glutaredoxin 5
- Defect in thiamine transporter 1
- Defect in mitochondrial proteins and exporters
- Can be X-linked, autosomal dominant, or autosomal recessive
RISK FACTORS
- Male gender (X-linked SA)
- Family history of hereditary SA
- Chronic alcohol abuse
GENERAL PREVENTION
Pyridoxine should be given to all patients on isoniazid to avoid anemia.
COMMONLY ASSOCIATED CONDITIONS
- Iron overload or secondary hemochromatosis from transfused blood products
- Transformation into acute leukemia is rare.
- Alcohol abuse
DIAGNOSIS
Moderate to severe anemia with fatigue, dizziness, and dyspnea should prompt an evaluation for SA.
HISTORY
- Symptoms of anemia, including fatigue, dizziness, and dyspnea (4)[A]
- Alcohol or drug exposures (4)[A]
- Toxin exposures (4)[A]
- Symptoms of iron overload (4)[A]
- Cardiac arrhythmias or heart failure related to iron overload (5)[A]
- Family history of anemia or myopathy, especially in men (4)[A]
- Patients can present with peripheral neuropathy or dermatitis if SA is related to pyridoxine deficiency (4)[A].
PHYSICAL EXAM
- No pathognomonic physical findings (4)[A]
- Signs of anemia, including tachycardia, conjunctival pallor (4)[A]
- Splenomegaly
DIFFERENTIAL DIAGNOSIS
- Thalassemias
- Iron deficiency anemia
- Folate or vitamin B12 deficiency
- Anemia of chronic disease
- Myelodysplastic syndromes
- Lead toxicity with anemia
- Copper deficiency
- Congenital disorders
- ALA dehydratase deficiency porphyria
- Congenital erythropoietic porphyria
- Hereditary coproporphyria
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- CBC
- Hypochromia with low mean corpuscular hemoglobin (MCH) (5)[A]
- Microcytosis with low mean corpuscular volume (MCV) in most cases (5)[A]
- Increased red cell distribution width (RDW) (5)[A]
- It is important to note that in SA related to myelodysplastic syndromes (MDS), normocytosis or macrocytosis may be seen (4)[A].
- Thrombocytosis may be seen with MDS (4)[A].
- Peripheral smear showing siderocytes with Pappenheimer bodies (hypochromic erythrocytes with basophilic iron deposits). Anisocytosis and poikilocytosis may be present:
- Basophilic stippling may be seen (4)[A].
- Iron studies are consistent with iron overload (5)[A]:
- Ferritin increased
- Serum iron levels increased
- Transferrin saturation increased
- Serum transferrin decreased
- Total iron-binding capacity (TIBC) normal
Follow-Up Tests & Special Considerations
- Serum copper, ceruloplasmin, serum zinc if suspected as cause (6)[A]
- Bone marrow evaluation reveals ringed sideroblasts, which is diagnostic for SA. Prussian blue staining also reveals ringed sideroblasts. Electron micrograph shows iron-filled mitochondria clustered around the nucleus (4)[A].
- Genetic analysis in patients with SA and microcytic anemia is necessary regardless of age (7)[B].
- Serum erythrocyte protoporphyrin is low in X-linked SA. This level is increased in X-linked SA with ataxia (5)[A].
- Liver biopsy is helpful to assess degree of iron overload (5)[A].
Diagnostic Procedures/Other
Bone marrow biopsy confirms the diagnosis of SA (5)[A].
Test Interpretation
- Bone marrow exam is the key diagnostic modality:
- Normoblastic erythroid hyperplasia
- Prussian blue iron stain showing ringed sideroblasts and 15-50% of erythroblasts with increased number of abnormally large granules ringing the nucleus (4)[A]
- Sideroblastic ring should cover at least 1/3 of the nucleus rim (4)[A].
- Electron microscopy reveals iron-overloaded mitochondria within erythroblasts (4)[A].
- Iron-laden macrophages (4)[A]
- Liver biopsy
- Iron deposition indistinguishable from hereditary hemochromatosis (5)[A]
TREATMENT
MEDICATION
First Line
- Treatment is largely supportive (5)[A].
- Pyridoxine
- Will improve anemia only in X-linked SA and alcohol-related SA (5)[A]
- Initial dose should be 50 to 100 mg PO daily (5)[A].
- Supplement folate to compensate for increased erythropoiesis if pyridoxine is effective (4)[A].
- Positive clinical response if reticulocytosis is seen within 2 weeks followed by increase in hemoglobin level over several months (4)[A].
- Combination therapy with erythropoietin and G-CSF can be helpful in acquired SA (4)[A].
- Blood transfusion based on symptoms of anemia. It may worsen iron overload and create need for iron chelation therapy (4)[A].
- Treatment for iron overload:
- Therapeutic phlebotomy can be considered (4)[A].
- Iron chelation therapy
- Deferoxamine 50 mg/kg/day in continuous 8- to 24-hour daily infusions (8)[A]
- Iron removal improved with addition of ascorbate. Due to cardiac, visual, and auditory toxicity, limit ascorbate intake to ≤200 mg/day (8)[A].
- Deferasirox is an oral once-daily iron chelator (9)[B].
- Recommended dose 20 to 40 mg/kg/day (9)[B]
- Long-term safety profile not well studied (9)[B]
- Side effects include skin rash, GI symptoms, and acute kidney injury (9)[B].
- Iron chelation therapy should be initiated when serum ferritin levels reach 1,000 ng/mL (10)[A].
- Removal of causative factors, such as alcohol, drugs, or toxins, should fully reverse SA (4)[A].
- Repletion of copper in patients with copper deficiency (6)[A]
ISSUES FOR REFERRAL
- Hematology consultation
- Genetic counseling is important for patients with heritable cause of SA (4)[A].
ADDITIONAL THERAPIES
Allogeneic stem cell transplantation has been successful in a few cases in younger patients with myelodysplastic syndromes (4)[A].
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Most patients without cardiac complications can be treated in the outpatient setting (5)[A].
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Annual ferritin and transferrin saturation to monitor for iron overload (4)[A]
- Patients given pyridoxine should be followed for response to treatment. Lab results should show reticulocytosis within 2 weeks and improved hemoglobin within 1 to 2 months (4)[A].
- Correction of nutritional deficiency
- Withdrawal of reversible cause
DIET
- Patients may need to avoid excessive alcohol intake.
- Patients with copper deficiency may need oral copper repletion.
PROGNOSIS
- More than half of X-linked SA with ALAS-2 mutations are pyridoxine-responsive (7)[B].
- Complications of iron toxicity avoided with proper iron overload therapy (4)[A]
- RARS: 40% of patients progress to acute leukemia often refractory to treatment (4)[A].
- When only the erythroid line is affected (PSA), progression to acute leukemia is not usually seen (4)[A].
- If SA follows treatment for malignancy, leukemic transformation is common (4)[A].
COMPLICATIONS
- Iron overload may cause organ damage:
- Cardiac arrhythmia or CHF (8)[A]
- Hepatic dysfunction (5)[A]
- Complication may arise from blood transfusions (4)[A].
REFERENCES
11 Willekens C, Dumezy F, Boyer T, et al. Linezolid induces ring sideroblasts. Haematologica. 2013;98(11):e138-e140. doi:10.3324/haematol.2013.092395.22 Shweta G, Prantesh J, Shashvat S. Isolated zinc deficiency causing severe microcytosis and sideroblastic anemia. Turk J Haematol. 2014;31(3):339-340.33 Chakraborty PK, Schmitz-Abe K, Kennedy EK, et al. Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD). Blood. 2014;124(18):2867-2871.44 Alcindor T, Bridges KR. Sideroblastic anaemias. Br J Haematol. 2002;116(4):733-743.55 Camaschella C. Hereditary sideroblastic anemias: pathophysiology, diagnosis, and treatment. Semin Hematol. 2009;46(4):371-377.66 May A, Fitzsimons E. Sideroblastic anaemia. Baillieres Clin Haematol. 1994;7(4):851-879.77 Ohba R, Furuyama K, Yoshida K, et al. Clinical and genetic characteristics of congenital sideroblastic anemia: comparison with myelodysplastic syndrome with ring sideroblast (MDS-RS). Ann Hematol. 2013;92(1):1-9.88 Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood. 1997;89(3):739-761.99 Porter J, Galanello R, Saglio G, et al. Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study. Eur J Haematol. 2008;80(2):168-176.1010 Bennet JM. Consensus statement on iron overload in myelodysplastic syndromes. Am J Hematol. 2008;83(11):858-861.
ADDITIONAL READING
- Cuijpers ML, van Spronsen DJ, Muus P, et al. Need for early recognition and therapeutic guidelines of congenital sideroblastic anaemia. Int J Hematol. 2011;94(1):97-100.
- M ¼ller-Berndorff H, Haas PS, Kunzmann R, et al. Comparison of five prognostic scoring systems, the French-American-British (FAB) and World Health Organization (WHO) classifications in patients with myelodysplastic syndromes: results of a single-center analysis. Ann Hematol. 2006;85(8):502-513.
- Rov ³ A, St ¼ssi G, Meyer-Monard S, et al. Sideroblastic changes of the bone marrow can be predicted by the erythrogram of peripheral blood. Int J Lab Hematol. 2010;32(3):329-335.
SEE ALSO
Algorithm: Anemia
CODES
ICD10
- D64.3 Other sideroblastic anemias
- D64.0 Hereditary sideroblastic anemia
- D64.1 Secondary sideroblastic anemia due to disease
- D64.2 Secondary sideroblastic anemia due to drugs and toxins
ICD9
285.0 Sideroblastic anemia
SNOMED
- Sideroblastic anemia (disorder)
- Hereditary sideroblastic anemia (disorder)
- Secondary acquired sideroblastic anemia (disorder)
- Alcohol-related sideroblastic anemia
CLINICAL PEARLS
- SA results from inability to incorporate iron during heme synthesis in the mitochondria, leading to microcytic anemia and sideroblasts in the bone marrow.
- Multiple inherited forms are linked to genetic mutations as well as acquired forms of SA.
- Patients may present with symptomatic anemia, with blood tests revealing iron overload.
- Bone marrow biopsy is required for diagnosis. Prussian blue staining reveals ringed sideroblasts.
- Treatment includes blood transfusions for symptomatic anemia, chelation therapy for iron overload, pyridoxine in X-linked SA and alcohol-related SA, and removal of causative factors if present.