Anemia- Sideroblastic




Sideroblastic anemia is caused by abnormal production of red blood cells (erythrocytes), usually as part of myelodysplastic syndrome, which can evolve into hematological malignancies (especially acute myelogenous leukemia). The body has iron available, but cannot incorporate it into hemoglobin. Abnormal red blood cells called sideroblasts are found in the blood of people with these anemias. Sideroblasts are seen, which are nucleated erythrocytes with granules of iron in their cytoplasm. Sideroblastic anemias are classified as hereditary, acquired, and reversible.


The symptoms of sideroblastic anemia are the same as for any anemia and iron overload. These may include fatigue, weakness, palpitations, shortness of breath, headaches, irritability, and chest pain. Physical findings may include pallor, tachycardia, hepatosplenomegaly, S3 gallop, jugular vein distension, and rales


The exact cause of sideroblastic anemia in many patients remains unknown. Reversible sideroblastic anemia can be caused by alcohol, isoniazid, pyrazinamide, cycloserine (a prescription antibiotic that may cause anemia, peripheral neuritis, or seizures by acting as a pyridoxine antagonist or increasing excretion of pyridoxine), chloramphenicol, or copper deficiency. The hereditary forms may be passed through families in autosomal recessive, autosomal dominant, or X-linked patterns.

The common feature of these causes is a failure to completely form heme molecules, whose biosynthesis takes place partly in the mitochondrion. This leads to deposits of iron in the mitochondria that form a ring around the nucleus of the developing red blood cell. Sometimes the disorder represents a stage in evolution of a generalized bone marrow disorder that may ultimately terminate in acute leukemia.

  • Toxins: lead or zinc poisoning
  • Drug-induced: ethanol, isoniazid, chloramphenicol, cycloserine
  • Nutritional: pyridoxine or copper deficiency
  • Genetic: ALA synthase deficiency (X-linked, associated with ALAS2)


The principle feature of sideroblastic anemia is slowly progressive, mild, life-long anemia which often goes unnoticed. Symptoms of iron overload may lead to the discovery of this underlying disorder. The history and clinical findings, together with laboratory findings, usually permit accurate diagnosis of each type. Laboratory evaluation may include complete blood count, iron studies, free erythrocyte protoporphyrin levels, MRI, bone marrow aspiration and liver biopsy. Molecular defects can be identified in several hereditary forms and in some patients with acquired sideroblastic anemia.

Sideroblastic anemias tend to be moderate to severe conditions with hemoglobin levels ranging usually from 4 to 10g/dl. Patients have the usual symptoms of anemia including fatigue, decreased tolerance to physical activity, and dizziness. Other symptoms and signs not related to anemia can also be present and may point to a cause of the condition (e.g. alcoholism). The history should include detailed questions concerning possible toxin or drug exposures, since these are reversible conditions. A detailed family history looking for anemia, particularly in male relatives, is important. Most hereditary sideroblastic anemias present in childhood. However, we are now recognizing milder cases of hereditary sideroblastic anemia whose symptoms do not draw attention until adulthood. Severe forms of most diseases are usually the first described. Over time, a broader clinical spectrum with mild or formes furstes of the conditions becomes apparent. No pathognomonic physical finding exists for sideroblastic anemia. The bone marrow picture in sideroblastic anemia was described earlier. The blood smear sometimes reveals basophilic stippling, hypochromia and microcytosis, although normocytosis and macrocytosis are possible, particularly in myelodysplastic syndromes. A dimorphic red cell population is characteristic of female carriers of the hereditary conditions. Iron deficiency can coexist with sideroblastic anemia. This scenario is particularly common in patients with myleodysplasia who can have chronic gastrointestinal bleeding due to platelet problems. Iron deficiency can mask sideroblastic anemia. Sideroblastic anemia remains in the differential diagnosis of patients with iron deficiency and anemia that is refractory to iron replacement. A repeat bone marrow following iron replacement can show ring sideroblasts not seen in the initial sample. Iron overload is more common than deficiency, however, even in patients without a significant blood product transfusion history. The exact cause of iron overload in sideroblastic anemia patients is unclear. Coexisting hemochromatosis gene mutations do not appear to be responsible (Beris et al, 1999). Ineffective erythropoiesis, as occurs with thalassaemia, can accelerate iron absorption from the gut. The ineffective erythropoiesis associated with sideroblastic anemia is much milder and does not completely explain the iron overload. Iron overload is a particular problem for patients with pure sideroblastic anemia. They are less likely to fall victim to the complications produced by myelodysplasia. Consequently, they can live long enough so that problems related to iron overload, including congestive heart failure and cirrhosis, become life-threatening issues.


The prognosis of sideroblastic anemia is highly variable. Reversible causes such as alcohol and drugs do not appear to carry long-term consequences. Patients requiring transfusions, those with conditions unresponsive to pyridoxine and other therapies, and those with a myelodysplastic syndrome that develops into acute leukemia have a poorer prognosis.

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. 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.


The treatment of sideroblastic anemia is directed at controlling symptoms of anemia and preventing organ damage from iron overload. Many patients see improvement with increased vitamin B6 intake - either through diet (potatoes, bananas, raisin bran cereal, lentils, liver, turkey, and tuna are good sources) or supplements - with red blood cell counts returning to near-normal values. Folic acid supplementation may also be beneficial. Those that do not respond to vitamin supplementation require blood transfusion.

A few small studies have described the use of allogenic bone marrow or stem cell transplantation for hereditary and congenital forms of sideroblastic anemia. While these therapies may offer the possibility of a cure, the complications associated with transplantation surgery must be considered.

All patients with sideroblastic anemia should be followed by a hematologist and avoid alcohol.

The first step in the treatment of sideroblastic anemia is to rule out reversible causes including alcohol or other drug toxicity, as well as exposure to toxins. The treatment of sideroblastic anemia is largely supportive, consisting primarily of blood transfusions to maintain an acceptable hemeoglobin level. A trial of pyridoxine at pharmacological doses (500mg per Os daily) is a reasonable intervention since it has few drawbacks and is an enormous benefit in those cases where it works (Murakami et al, 1991). A complete response to pyridoxine generally occurs in cases resulting from ethanol abuse or the use of pyridoxine antagonists. Discontinuation of the offending agent hastens recovery. Some patients with hereditary, X-linked sideroblastic anemia also respond to pyridoxine. Improvement with pyridoxine is rare for sideroblastic anemias of other etiologies. After obtaining baseline parameters (red cell indices, iron studies), the initial dose of pyridoxine should be 100-200mg daily by mouth with a gradual escalation to a daily dose of 500mg. Folic acid supplementation compensates for possible increased erythropoiesis, should the pyridoxine work. A reticulocytosis occurs within 2 weeks in responsive cases, followed by a progressive increase in the hemoglobin level over the next several months. The maintenance dose of pyridoxine is that which maintains a steady-state hemoglobin level. Microcytosis often persists, but is of no clinical significance. Except in toxin-induced cases, pyridoxine treatment is usually indefinite. Patient compliance or drug side effects can limit the treatment regimen. Fortunately, side effects are rare with daily doses of less than 500mg. Some patients on doses in excess of 1000mg daily have developed a reversible peripheral neuropathy. In responsive patients, anemia recurs with discontinuation of the pyridoxine. Many patients with sideroblastic anemia require chronic transfusion to maintain acceptable hemoglobin levels. Patient symptoms rather than an absolute hemoglobin level or hematocrit should guide transfusion. This will limit the adverse consequences of transfusion, which include transmission of infections, allo-immunization and secondary hemeochromatosis. Even in patients with no meaningful transfusion history, some authorities advocate yearly monitoring of the ferritin level and transferrin saturation. Iron chelation with desferrioxamine is the standard treatment for transfusional hemeochromatosis. Occasionally, patients with a modest anemia (e.g., hemeoglobin=10 g/dL) who are not transfusion-dependent will tolerate small-volume phlebotomies to remove iron. In some cases, the anemia improves with removal of excess iron (Hines, 1976; French et al, 1976). This could reflect a reduction in mitochondrial injury by iron-mediated reactive oxygen species. This is pure speculation, however, and the scenario is distinctly unusual. Anecdotal reports and small case series describe allogeneic bone marrow or stem cell transplantation for sideroblastic anemia (Gonzalez et al, 2000; Urban et al, 1992). The obvious advantage is the possibility of cure, as has occurred in patients with ß-thalassemia. Possible cure must be balanced against transplant complications, particularly in older people. Families with severe forms of hereditary sideroblastic anemia should receive genetic counseling.


  • NIH