What are ring sideroblasts?

Ring sideroblasts are red cell precursors (erythroblasts) in the bone marrow whose mitochondria are packed with iron that could not be built into heme. Because those mitochondria sit around the nucleus, a Prussian blue (Perls) iron stain shows a ring of iron granules; the formal definition is at least 5 granules encircling at least one-third of the nucleus. They define sideroblastic anemia and are absent in iron deficiency and anemia of chronic disease.

What do iron studies show in sideroblastic anemia?

Iron studies show iron overload rather than deficiency: a high serum iron, transferrin saturation above 50% and ferritin often above 400 ng/mL, with a normal TIBC. The RDW is high because small and normal-sized red cells circulate together. This separates it from iron deficiency (low ferritin, high TIBC, saturation below 10%) and from anemia of chronic disease, where serum iron and saturation are low or normal while ferritin is high.

What causes sideroblastic anemia?

Inherited forms are less common than acquired ones, and the most common inherited form is X-linked sideroblastic anemia from ALAS2 mutations. Acquired causes include myelodysplastic neoplasms with SF3B1 mutations in older adults, alcohol, drugs such as isoniazid, linezolid, chloramphenicol, cycloserine and pyrazinamide, vitamin B6 deficiency, copper deficiency (for example from excess zinc or bariatric surgery) and lead. Removing the toxin or drug, or replacing pyridoxine or copper, can reverse the acquired types.

Why does isoniazid cause sideroblastic anemia?

Isoniazid inactivates pyridoxine (vitamin B6). Its active form, pyridoxal phosphate, is the cofactor for ALA synthase, which makes delta-aminolevulinic acid from glycine and succinyl-CoA in the first, rate-limiting step of heme synthesis. With too little heme, iron accumulates in erythroblast mitochondria and forms ring sideroblasts. Pyridoxine treats it, and most people taking isoniazid are given pyridoxine routinely, which also prevents peripheral neuropathy.

Is sideroblastic anemia microcytic or macrocytic?

It depends on the cause. Inherited forms such as X-linked sideroblastic anemia are usually microcytic and hypochromic, which is why exam questions list sideroblastic anemia with the microcytic anemias. Acquired sideroblastic anemia from myelodysplastic neoplasms is usually normocytic or macrocytic. Many patients have two red cell populations, small hypochromic cells mixed with normal or large cells, so the RDW is high even when the MCV is normal.

What is MDS with SF3B1 mutation?

It is a myelodysplastic neoplasm, usually lower risk, defined by a mutation in the splicing-factor gene SF3B1 with fewer than 5% marrow blasts and no 5q deletion, monosomy 7 or complex karyotype. The 2022 WHO classification calls it MDS with low blasts and SF3B1 mutation and lets 15% or more ring sideroblasts substitute for the mutation; the ICC calls it MDS with mutated SF3B1. Anemia is treated with transfusion, erythropoiesis-stimulating agents or luspatercept.

Sideroblastic Anemia: Ring Sideroblasts, Iron Studies, INH

Sideroblastic anemia is an iron-utilization anemia: heme synthesis fails, so iron that cannot be inserted into protoporphyrin IX piles up in the mitochondria of marrow erythroblasts and forms ring sideroblasts on Prussian blue (Perls) iron stain. Iron studies are the mirror image of iron deficiency: high serum iron, transferrin saturation and ferritin with a normal TIBC. The most common inherited form is X-linked (ALAS2 mutations) and microcytic; acquired causes are myelodysplastic neoplasm with an SF3B1 mutation (usually normocytic or macrocytic), alcohol, isoniazid and other drugs, vitamin B6 or copper deficiency (for example from excess zinc), and lead.

Quick check · free practice questionStep 1

A 42-year-old man with HIV infection who has been inconsistently taking his antiretroviral medications presents with a 2-month history of malaise and unintentional 12-lb weight loss. Over the past 2 weeks, he has developed cough, night sweats, and subjective fevers. A chest radiograph shows a cavitary lesion in the left upper lobe, and an interferon-gamma release assay is positive. He is started on appropriate antimicrobial therapy. One month later, he returns for follow-up. Laboratory evaluation shows leukocytosis with a normal differential, anemia, thrombocytosis, and microcytosis. Peripheral blood smear demonstrates Pappenheimer bodies. Labs: - Leukocyte count: 11,000/mm^3 - Hemoglobin: 9.2 g/dL - Platelet count: 400,000/mm^3 - Mean corpuscular volume (MCV): 75 µm^3 Which of the following is the most accurate diagnostic test for this patient’s condition?

The question

A 54-year-old man has 3 months of progressive fatigue and shortness of breath on exertion. He has alcohol use disorder and drinks 6-8 beers daily. Four months ago he started isoniazid for latent tuberculosis; pyridoxine was not prescribed. He is pale. Hemoglobin is 8.9 g/dL, MCV 72 fL and RDW increased. Serum iron and ferritin are increased, TIBC is normal and transferrin saturation is 78%. The blood smear shows a dimorphic population of hypochromic microcytes and normal-sized red cells, some containing small granules. Blood lead concentration is normal. A bone marrow aspirate stained with Prussian blue shows erythroid precursors with iron granules encircling the nucleus.

Which of the following best explains this patient's anemia?

A. Decreased synthesis of globin chains B. Depleted iron stores from chronic blood loss C. Hepcidin-mediated trapping of iron in macrophages D. Impaired δ-aminolevulinic acid synthesis due to pyridoxal phosphate deficiency E. Lead inhibition of δ-aminolevulinic acid dehydratase and ferrochelatase F. Impaired DNA synthesis from folate deficiency

Answer and every choice explained

Answer: D. This is acquired sideroblastic anemia. Pyridoxal phosphate (active vitamin B6) is the cofactor for ALA synthase, which joins glycine and succinyl-CoA to make δ-aminolevulinic acid (δ-ALA), the first and rate-limiting step of heme synthesis (ALAS2 is the red-cell form). Isoniazid inactivates pyridoxine, and alcohol use disorder both causes B6 deficiency and acts as a marrow toxin. Without heme, iron keeps entering erythroblast mitochondria with nowhere to go: ring sideroblasts in the marrow, iron overload on blood tests. Dimorphic red cells explain the high RDW.

Management: stop alcohol, give pyridoxine and stop or replace the offending drug; the anemia can recover once the cause is removed. Do not give iron. Most people taking isoniazid should receive pyridoxine anyway (Merck suggests 30-50 mg/day), to prevent neuropathy as well as anemia (see the tuberculosis breakdown).

A. Globin chain synthesis (thalassemia): microcytic, often with a high red cell count and target cells; beta-thalassemia minor shows Hb A2 above 3.5%. Ring sideroblasts and iron overload are not features of thalassemia trait, and this anemia began in middle age with a clear trigger. Compare in the thalassemia table.
B. Iron deficiency: ferritin below 30 ng/mL, transferrin saturation below 10%, high TIBC and absent marrow iron, the opposite of this patient. Microcytosis with a high ferritin is not iron deficiency (see the iron deficiency anemia breakdown).
C. Hepcidin (anemia of chronic disease): inflammation raises hepcidin, so serum iron and transferrin saturation are low or normal while ferritin is above 100 ng/mL; the anemia is often normocytic. A high serum iron and a saturation of 78% rule it out (anemia of chronic disease).
E. Lead: lead does block δ-ALA dehydratase and ferrochelatase, can produce basophilic stippling and ring sideroblasts, and causes a normocytic or microcytic anemia. But the blood lead level is normal, and the stem gives no exposure history, abdominal pain, constipation or neuropathy. Whole blood lead level is the diagnostic test.
F. Folate deficiency: alcohol tempts you toward folate, but folate (or B12) deficiency causes a macrocytic, megaloblastic anemia and no ring sideroblasts.

Iron studies: the microcytic anemia grid

Finding	Iron deficiency	Anemia of chronic disease	Thalassemia trait	Sideroblastic anemia
MCV	Low	Often normal, can be low	Low, with a high RBC count	Low in inherited forms; normal or high in MDS
RDW	High	Normal or slightly high	Often normal	High (dimorphic cells)
Serum iron	Low	Normal or low	Normal	High
TIBC	High	Normal or low	Normal	Normal
Transferrin saturation	Below 10%	Normal or low	Normal	Above 50%
Ferritin	Below 30 ng/mL	Above 100 ng/mL	Normal	Above 400 ng/mL
Marrow iron	Absent	Present	Present	Increased, ring sideroblasts
Smear clue	Hypochromic microcytes	Unremarkable	Target cells	Dimorphic cells, stippled cells, Pappenheimer bodies
Confirm with	Ferritin, then find the source	Clinical context	Hb electrophoresis (Hb A2 above 3.5% in beta trait); DNA testing for alpha trait	Marrow iron stain; SF3B1 testing in older adults

Iron deficiency, anemia of chronic disease and sideroblastic values are from Merck's microcytic-anemia table; the thalassemia column is the standard exam pattern.

What a ring sideroblast is

An erythroblast with 5 or more iron granules encircling at least one-third of the nucleus, seen on Prussian blue (Perls) stain of a marrow aspirate.
The granules are iron-loaded mitochondria, which sit around the nucleus.
Don't confuse it with Pappenheimer bodies (iron granules inside circulating red cells, called siderocytes) or basophilic stippling (fine blue dots on a routine smear; common but not specific in lead poisoning, and also seen in sideroblastic anemia and thalassemia).

Heme synthesis: where each cause hits

Step	Enzyme	Disrupted by
Glycine + succinyl-CoA → δ-ALA (mitochondria, rate-limiting)	ALA synthase (ALAS2 in red cells), needs pyridoxal phosphate	ALAS2 mutation, B6 deficiency, isoniazid, alcohol
δ-ALA → porphobilinogen	δ-ALA dehydratase (porphobilinogen synthase)	Lead
Fe²⁺ + protoporphyrin IX → heme (mitochondria)	Ferrochelatase	Lead: zinc is inserted instead, raising zinc protoporphyrin

Because lead blocks δ-ALA dehydratase, the enzyme that consumes δ-ALA (and less heme means less feedback restraint on ALA synthase), δ-ALA builds up and can be found in excess in the urine.

Causes of ring sideroblasts and the clue that gives each away

Cause	Classic clue	Key point	Treatment
X-linked sideroblastic anemia (ALAS2)	Boy or young man with microcytic anemia and iron overload; carrier women can develop it later in life	Most common inherited form	Pyridoxine (often a partial response); treat iron overload
MDS with SF3B1 mutation	Older adult, normocytic or macrocytic anemia, usually lower-risk MDS; with thrombocytosis, think MDS/MPN with SF3B1 mutation and thrombocytosis	Somatic splicing-factor mutation	Transfusion, erythropoiesis-stimulating agents, luspatercept, iron chelation
Alcohol	Heavy drinking	Marrow toxin and cause of B6 deficiency	Abstinence
Drugs: isoniazid, linezolid, chloramphenicol, cycloserine, pyrazinamide	TB or long antibiotic course	Isoniazid and cycloserine inactivate pyridoxine	Stop or replace the drug; pyridoxine
Copper deficiency	Excess zinc, bariatric surgery or malabsorption; anemia with neutropenia and a B12-like myeloneuropathy	Zinc blocks copper absorption	Stop zinc, give oral copper (copper deficiency mnemonic)
Lead	Old paint, ceramic glaze, moonshine, retained bullets; abdominal pain, neuropathy, cognitive deficits	Blocks δ-ALA dehydratase and ferrochelatase	Remove the source; chelation for high levels

Untreated iron overload damages the heart and liver, so patients who are iron-overloaded need chelation, or phlebotomy if the anemia allows.

MDS with SF3B1: the current names

WHO 5th edition (2022) renamed myelodysplastic syndromes myelodysplastic neoplasms and defined MDS with low blasts and SF3B1 mutation (MDS-SF3B1): an SF3B1 mutation, fewer than 5% marrow and 2% blood blasts, and no 5q deletion, monosomy 7 or complex karyotype. It covers more than 90% of MDS with 5% or more ring sideroblasts.
Ring sideroblasts of 15% or more can substitute for the mutation; "MDS with low blasts and ring sideroblasts" is the accepted term for SF3B1-wild-type cases. The old "MDS/MPN with ring sideroblasts and thrombocytosis" is now MDS/MPN with SF3B1 mutation and thrombocytosis.
ICC (2022) uses "MDS with mutated SF3B1", defined by the mutation (variant allele fraction 10% or more, no RUNX1 co-mutation) rather than the ring sideroblast count.
Luspatercept is an erythroid maturation agent that traps TGF-β superfamily ligands. Its FDA label covers anemia in very low- to intermediate-risk MDS in patients who have not had an erythropoiesis-stimulating agent and may need regular transfusions, and in MDS with ring sideroblasts (or MDS/MPN-RS-T) after such an agent fails, when 2 or more red cell units are needed over 8 weeks. It is also approved for transfusion-dependent beta-thalassemia.

More on MDS in the myelodysplastic syndromes breakdown.

How USMLE tests it

"Microcytic anemia with high iron and high ferritin" is the classic exam signal for sideroblastic anemia. In practice, inherited forms are usually microcytic, while MDS-related forms are usually normocytic or macrocytic, often with a dimorphic smear.
INH plus a new anemia or neuropathy: think pyridoxine.
High ferritin alone is not enough: anemia of chronic disease also has high ferritin, but serum iron and saturation are low.
Copper deficiency mimics B12 deficiency (anemia plus myeloneuropathy) and adds neutropenia; ask about zinc.
Never treat ring sideroblasts with iron.

Key takeaways

Sideroblastic anemia = defective heme synthesis with iron trapped in erythroblast mitochondria: ring sideroblasts on Prussian blue stain.
Labs: high serum iron, transferrin saturation above 50%, high ferritin, normal TIBC, high RDW from dimorphic cells.
Inherited: X-linked ALAS2 (microcytic, pyridoxine-responsive in part). Acquired: MDS with SF3B1 mutation (normocytic or macrocytic), alcohol, isoniazid and other drugs, B6 or copper deficiency (zinc excess), lead.
ALA synthase needs pyridoxal phosphate; lead blocks δ-ALA dehydratase and ferrochelatase.
Treat the cause: stop alcohol and drugs, give pyridoxine or copper, treat MDS (ESAs, luspatercept, transfusion); manage iron overload, and never give iron.
WHO 2022: MDS with low blasts and SF3B1 mutation; ICC 2022: MDS with mutated SF3B1.