Ring sideroblasts are an unusual finding in bone marrow cells, signifying a disruption in how the body handles iron within developing red blood cells. Their presence always indicates underlying pathological conditions. This article clarifies their nature, formation, associated health conditions, and how they are identified.
What Are Ring Sideroblasts?
Ring sideroblasts are abnormal red blood cell precursors, specifically erythroblasts, found in the bone marrow. These cells are characterized by an accumulation of iron granules that form a distinctive ring around the nucleus. According to the International Working Group on Morphology of Myelodysplastic Syndrome (IWGM-MDS), an erythroblast is classified as a ring sideroblast if it contains at least five siderotic granules covering a minimum of one-third of the nucleus’s circumference.
The iron within these granules is not incorporated into hemoglobin. Instead, this excess non-heme iron accumulates within the mitochondria, the cell’s powerhouses. After a special staining procedure called Prussian blue, these iron-loaded mitochondria appear as blue granules, clearly outlining the nucleus. This appearance distinguishes them from normal sideroblasts, which are healthy erythroblasts with a few scattered iron granules in their cytoplasm, representing iron stored in cytosolic ferritin, not in the mitochondria.
How Ring Sideroblasts Form
The formation of ring sideroblasts stems from a disruption in the body’s ability to properly utilize iron for hemoglobin synthesis. Iron is absorbed and transported to developing red blood cells in the bone marrow, where it is normally incorporated into heme, a component of hemoglobin. This process occurs within the mitochondria of erythroblasts.
When heme synthesis or iron utilization pathways are defective, iron cannot be efficiently incorporated into hemoglobin. Instead, it builds up inside the mitochondria of these developing red blood cells. This mitochondrial iron overload leads to the characteristic “ring” formation. The inability to properly use iron for hemoglobin production results in ineffective erythropoiesis, meaning the bone marrow produces fewer healthy red blood cells.
Health Conditions Associated with Ring Sideroblasts
The presence of ring sideroblasts is a hallmark of sideroblastic anemias, a group of diverse disorders characterized by impaired iron utilization during red blood cell development. These conditions can be broadly categorized into inherited and acquired forms.
Inherited Forms
Inherited forms, though less common, include X-linked sideroblastic anemia (XLSA), which is caused by mutations in the ALAS2 gene. This mutation leads to insufficient hemoglobin synthesis and iron accumulation. XLSA often presents with microcytic (small) and hypochromic (pale) red blood cells, and can lead to iron overload in various organs.
Acquired Forms
Acquired forms are more frequent and can arise from various causes. Myelodysplastic syndromes (MDS) are a significant group of acquired conditions where ring sideroblasts are often found. “Refractory anemia with ring sideroblasts” (RARS) is a subtype of MDS defined by anemia and the presence of 15% or more ring sideroblasts in the bone marrow. Other acquired causes include chronic alcohol abuse, certain medications like isoniazid, and deficiencies of specific nutrients such as copper or pyridoxine (vitamin B6). Alcohol can interfere with pyridoxine metabolism, leading to ring sideroblasts. Copper deficiency can also induce ring sideroblasts.
Identifying Ring Sideroblasts
Identifying ring sideroblasts involves a bone marrow examination, which includes both a bone marrow aspirate and a biopsy. A small sample of bone marrow is collected, usually from the hip bone. The sample is then stained to visualize the iron deposits.
The most common stain used is the Prussian blue stain, also known as Perls’ reaction. This stain reacts with iron, causing it to appear as blue or green-blue granules. Pathologists then examine the stained bone marrow aspirate smears to confirm the presence and percentage of ring sideroblasts. While ring sideroblasts do not cause specific symptoms, their presence prompts further investigation into the underlying condition, which often manifests as anemia, leading to symptoms like fatigue and pallor.