Sideroblastic Anemia

Article written and reviewed by Dr Luca Moretti

Sideroblastic anemia comprises a heterogeneous group of hematologic disorders characterized by ring sideroblasts in the bone marrow, namely erythroblasts with pathologic iron accumulation in mitochondria. This condition reflects a defect in heme synthesis, resulting in ineffective erythropoiesis and progressive dysfunction of iron utilization despite often increased iron stores. Sideroblastic anemias may occur in congenital or acquired forms, affect all age groups and show an extremely variable clinical spectrum, ranging from mild and asymptomatic disease to severe transfusion-dependent forms complicated by iron overload. Diagnosis requires precise integration of clinical, laboratory and morphologic data, and therapeutic management is strongly influenced by the underlying etiology and prompt identification of complications.

Etiology, pathogenesis and pathophysiology

Sideroblastic anemia may result from congenital or acquired causes, each with specific pathogenic mechanisms that ultimately impair the ability of erythroid precursors to incorporate iron correctly into heme. Heme synthesis is a complex process occurring between mitochondria and cytosol in erythroblasts, with the first and final steps located in mitochondria: a defect in any enzymatic step, mitochondrial transporter or required cofactor can produce a functional block and perinuclear iron accumulation.

The congenital forms, although rare, are clinically important and are often caused by mutations in genes essential for heme synthesis, such as ALAS2 in the X-linked form, or genes involved in mitochondrial iron metabolism, including SLC25A38, GLRX5 and ABCB7. In these inherited variants, onset may occur early and, in some syndromes, may be associated with extrahematologic manifestations such as deafness, ataxia, growth delay or skeletal abnormalities.

More common are the acquired forms, seen mainly in adults and older people. The principal cause is represented by myelodysplastic syndromes (MDS) with ring sideroblasts, often associated with mutations in SF3B1 that profoundly alter erythroid maturation. Other acquired causes include chronic alcohol exposure, prolonged use of certain medications such as isoniazid, linezolid, chloramphenicol and chemotherapy agents, lead poisoning, vitamin B6 deficiency and copper deficiency, including copper deficiency secondary to zinc excess. In these cases the defect may be reversible if the causative agent is identified and removed promptly.

The risk of developing sideroblastic anemia increases in the presence of predisposing factors such as advanced age, chronic alcohol consumption, occupational exposure to environmental toxins, therapy with myelotoxic drugs or antagonists of heme synthesis, malnutrition, particularly pyridoxine deficiency, and a personal or family history of hematologic diseases.

The central pathophysiologic mechanism is mitochondrial iron accumulation within erythroblasts. Normally, iron carried by transferrin is internalized and transferred to mitochondria, where it is incorporated into protoporphyrin IX to form heme. A functional block at any level, from reduced enzymatic activity such as ALA synthase deficiency to defects in mitochondrial transporters or iron-sulfur clusters, prevents iron from being used for heme synthesis, causing its characteristic accumulation around the nucleus. This finding, demonstrable with Perls staining, defines ring sideroblasts but must be interpreted within the etiologic and classification context.

Ineffective erythropoiesis causes chronic anemia, which may be microcytic, normocytic, macrocytic or dimorphic depending on the form, together with progressive activation of compensatory mechanisms that enhance intestinal iron absorption and further worsen iron overload. Systemically, excess iron can deposit in several organs, including the liver, heart, pancreas and endocrine glands, eventually producing true secondary hemosiderosis, one of the major complications and prognostic determinants of the disease.

Clinical manifestations

The clinical presentation of sideroblastic anemia is extremely variable and depends on whether the form is congenital or acquired, the severity of anemia and the rate of onset. Presentation may be insidious, with symptoms of chronic anemia such as fatigue, weakness, exertional dyspnea, tachycardia and palpitations, while more severe forms, particularly in transfusion-dependent patients, may progress to heart failure or angina. Physical examination often reveals cutaneous and mucosal pallor, sometimes mild jaundice and, in chronic forms, signs of iron overload such as hepatomegaly and skin pigmentation.

In patients with myelodysplastic syndromes, symptoms may also include manifestations of neutropenia, such as recurrent infections, thrombocytopenia, such as mucocutaneous bleeding, and systemic manifestations including weight loss, night sweats and bone pain. Children with congenital forms may present, in addition to anemia, with growth delay, deafness, ataxia, neurologic abnormalities or skeletal abnormalities, depending on the responsible mutation.

As the disease progresses and iron overload increases, organ complications appear: chronic liver disease with hepatomegaly, fibrosis and cirrhosis, iron-overload cardiomyopathy with arrhythmias and heart failure, diabetes mellitus and various endocrinopathies such as hypogonadism and hypothyroidism. These complications, often subtle and nonspecific in the early stages, become progressively more severe and affect long-term prognosis.

Diagnosis and investigations

Sideroblastic anemia should be suspected in microcytic, normocytic, macrocytic or dimorphic anemia, depending on the form, that does not respond to iron therapy and is associated with paradoxically increased iron indices, including elevated serum iron, ferritin and transferrin saturation. A detailed medical history investigating exposure to medications and toxins, alcohol consumption, chronic diseases and family history of hematologic disorders is essential to guide the diagnostic work-up.

The peripheral blood smear often shows hypochromic erythrocytes and anisopoikilocytosis, sometimes target cells and basophilic stippling. Definitive diagnosis, however, is based on bone marrow examination, which shows an increased proportion of ring sideroblasts, erythroblasts with mitochondrial iron accumulation demonstrable by Perls staining. Diagnosis requires ring sideroblasts in the bone marrow together with determination of the cause. In MDS, criteria depend on the 2022 WHO/ICC classification and the presence of an SF3B1 mutation; a universal threshold above 15% does not apply to all entities.

Laboratory tests show, in addition to anemia, often increased ferritin and serum iron, increased transferrin saturation and normal or reduced TIBC. In pediatric patients and cases in which an inherited form is suspected, genetic testing of relevant genes such as ALAS2 and SLC25A38 can confirm the diagnosis and guide family counseling.

In myelodysplastic forms, it is necessary to extend investigations to specific mutations, particularly SF3B1, while blood lead levels and basophilic stippling are assessed in people exposed to lead. In compatible cases, serum copper and ceruloplasmin should also be evaluated and excessive zinc exposure investigated. Assessment of systemic iron burden by serum ferritin and tissue MRI of the liver and heart is essential for early identification of organ iron deposition.

The differential diagnosis includes iron deficiency anemia, in which iron stores are reduced and sideroblasts are absent, thalassemias and other dyserythropoietic anemias. Involvement of hematology, genetics and hepatology specialists is recommended in complex or pediatric cases.

Treatment and prognosis

Management of sideroblastic anemia is based on removal of the cause when possible, treatment of anemia and prevention of complications from iron overload. In acquired forms, withdrawal of causative drugs or toxins, abstinence from alcohol and, when indicated, vitamin B6 (pyridoxine) supplementation are effective strategies, particularly in nutritional deficiencies or drug-related responsive forms; in congenital X-linked forms caused by ALAS2 variants, pyridoxine may be effective in responsive patients.

When anemia is severe and symptomatic, transfusion support may be required but must be carefully balanced against the risk of iron accumulation. In myelodysplastic syndromes, treatment includes erythropoiesis-stimulating agents such as EPO or darbepoetin, luspatercept in patients who meet the regulatory indication for very low-, low- or intermediate-risk MDS with transfusion-dependent anemia, and hematopoietic stem cell transplantation in eligible patients.

Iron overload is managed with iron chelation therapy such as deferasirox or deferoxamine, particularly in transfusion-dependent patients or those with persistently elevated ferritin. Periodic monitoring of ferritin and hepatic and cardiac function is essential, together with magnetic resonance imaging to quantify tissue iron deposits.

Prognosis depends closely on the underlying cause, age at onset and how promptly appropriate therapy is started. Pyridoxine-responsive hereditary forms have a favorable course, whereas MDS carries a risk of progression to acute leukemia and complications related to systemic iron overload.

Complications

Complications of sideroblastic anemia result from both chronic anemia and progressive iron accumulation, which can damage multiple organs and systems. Hematologic manifestations include severe anemia and, in MDS, pancytopenia and a risk of leukemic progression. If not managed promptly, iron overload causes hepatic hemosiderosis with fibrosis and cirrhosis, iron-overload cardiomyopathy with heart failure and arrhythmias, diabetes mellitus and other endocrinopathies such as hypogonadism and hypothyroidism.

In some pediatric congenital syndromic forms, growth delay, neurologic manifestations, skeletal malformations and multisystem abnormalities may occur. Infectious complications are frequent in advanced stages of MDS because of concomitant neutropenia and immunosuppression.

Multidisciplinary management and long-term surveillance are essential to limit morbidity, improve survival and preserve quality of life in patients with sideroblastic anemia.

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