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. Sideroblasts are seen, which are nucleated erythrocytes with granules of iron in their cytoplasm.

Etiology- Pathology

• Sideroblastic anemia is an enzyme disorder in which the body has adequate iron but is unable to incorporate it into hemoglobin.
• Iron enters the developing red blood cell (erythroblasts); here iron accumulates in the mitochondria giving a ringed appearance to the nucleus (ringed sideroblast). The mitochondria are overloaded with iron and hemoglobin production (heme synthesis) is defective.
• Sideroblasts are not pathognomonic of any one disease but rather are a bone marrow manifestation of several diverse disorders. 
• On a marrow stained with Prussian blue, a sideroblast is an erythroblast that has stainable deposits of iron in cytoplasm.
• Progesterone and pregnancy have been reported to induce relapse of sideroblastic anemia.

Clinical types

• Congenital Sideroblastic anemia
• X- linked Sideroblastic anemia

 

Of the congenital sideroblastic anemias, X-linked sideroblastic anemias are further divided into pyridoxine-responsive and pyridoxine-resistant subtypes. 

 

• In the pyridoxine-responsive type of congenital sideroblastic anemia, point mutations on the X chromosome have been identified that result in a δ-amino levulinic acid synthase (ALAS-2) with very low enzymatic activity.
• A prototype of pyridoxine-resistant, X-linked sideroblastic anemia is the ABC7 gene mutation.
• In contrast to the pyridoxine-responsive sideroblastic anemia, the ABC7 defect has a nonprogressive cerebellar ataxia component with diminished deep-tendon reflexes, incoordination, and elevated free erythrocyte protoporphyrin

 

Autosomal recessive sideroblastic anemia has been described in conjunction with mitochondrial myopathy and lactic acidosis

An autosomal dominantly inherited form also exists but is extremely rare

Pearson (marrow pancreas) syndrome

Its a juvenile, multisystem disorder caused by deletions in mitochondrial DNA (mtDNA) manifested as severe, refractory sideroblastic anemia, neutropenia, vacuolated cells in bone-marrow precursors, exocrine pancreas insufficiency, malabsorption, and growth failure.

DIDMOAD syndrome

DIDMOAD syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness syndrome) is associated with sideroblastic anemia that is responsive to vitamin B-1 (thiamine). The proposed etiology of DIDMOAD syndrome is an inherited defect in thiamine metabolism.

Acquired sideroblastic anemia

• Of the acquired sideroblastic anemias, refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome characterized by an anemia in which at least 15% of bone marrow erythroblasts are ringed sideroblasts.
• Approximately 15% of these patients also have thrombocytosis.
• Copper deficiency
• Vitamin B-6 (pyridoxine) deficiency
• Lead poisoning
• Zinc over dose
• Excessive alcohol consumption
• Drugs reported to cause sideroblastic anemia- Fusidic acid, Tetracycline, Isoniazid, Progesterone replacement, Phenacetin, D- penicillamine and chemotherapy drugs
• Hypothermia
• Idiopathic

Clinical features

• Incoordination (cerebellar symptoms)
• Failure of growth
• Diarrhea (malabsorption)
• Polyuria, blindness, deafness (associated with DIDMOAD syndrome)
• History of exposure to cold for prolonged periods
• Family history of mitochondrial disease and anemia
• Chronic dialysis with higher than normal zinc levels
• General symptoms of anemia, including malaise, fatigue, and dyspnea on exertion

Tests and diagnosis

• Anemia, mostly moderate, although severe anemia has been reported
• The mean corpuscular volume (MCV) is usually low, with a microcytic picture;
• The peripheral smear may exhibit basophilic stippling in cases of lead poisoning
• Iron studies may show increased a ferritin, high transferrin saturation level with decreased total iron-binding capacity (TIBC).
• Specific test: Prussian blue stain of RBC in marrow. Shows ringed sideroblasts.
• Bone marrow aspiration and biopsy

Treatment

• Pyridoxine (vitamin B-6) deserves a trial in all cases of sideroblastic anemia as many acquired and certain congenital forms of sideroblastic anemia respond to this relatively safe drug.
• Pyridoxal phosphate (P5'P) is an active form of pyridoxine and has been successfully used in the treatment of sideroblastic anemias in some cases that are unresponsive to pyridoxine.
• Thiamine (vitamin B-1) works by an incompletely understood mechanism to correct sideroblastic anemia in DIDMOAD syndrome.
• Folic acid has been reported to solely reverse sideroblastic changes in some patients
• Chloroquine has been successfully used to treat pyridoxine-resistant sideroblastic anemia

Transfusion

• Transfusion is the mainstay of treatment for those whose sideroblastic anemia does not respond to pyridoxine therapy.
• Transfusion is problematic and should be avoided if the anemia is mild to moderate and the patient asymptomatic
• Even in the absence of transfusion, patients with sideroblastic anemia are prone to develop iron overload
• Transfusion in sideroblastic anemia has been known to worsen iron overload and lead to secondary hemochromatosis and cirrhosis. 
• Iron overload in sideroblastic anemia can be fatal
• Desferrioxamine can be used if iron overload develops from repeated blood transfusions
• Deferasirox is a relatively new, oral iron chelator that is being used nowadays
• Phlebotomy can be performed for iron overload

Bone marrow transplantation

Bone marrow transplantation is a treatment of last resort and is best saved for young patients whose conditions are pyridoxine resistant, transfusion dependent.