Sideroblastic anemia

Summary

Sideroblastic anemia is a group of disorders in which the bone marrow fails to incorporate iron into hemoglobin, leading to iron overload inside mitochondria of red cell precursors (forming ringed sideroblasts) and ineffective erythropoiesis.

• Type: usually microcytic anemia (can be normocytic or dimorphic).
• Causes: congenital (X-linked, ALAS2 defect) or acquired (alcohol, lead, isoniazid, chloramphenicol, copper deficiency, myelodysplastic syndrome).
• Hallmark labs: ↑ serum iron, ↑ ferritin, ↑ transferrin saturation, ↓ TIBC — the opposite of iron deficiency anemia.
• Smear: basophilic stippling (in lead poisoning); marrow: ringed sideroblasts on Prussian blue stain.
• Treatment: remove the cause + pyridoxine (vitamin B6) for hereditary and isoniazid-induced forms.

Definition

Sideroblastic anemia is a heterogeneous group of disorders characterized by:

• Defective heme synthesis inside erythroblasts (red cell precursors).
• Accumulation of iron in mitochondria surrounding the nucleus → ringed sideroblasts (the diagnostic finding on bone marrow Prussian blue stain).
• Ineffective erythropoiesis → cells die in the marrow before being released → anemia despite plenty of iron.

Because heme cannot be made, hemoglobin synthesis fails and the RBCs are usually microcytic and hypochromic. However, the body still absorbs iron normally → systemic iron overload develops with time (similar to hemochromatosis).

Etiology

Causes are divided into hereditary and acquired (the acquired group is far more common in clinical practice and in exam questions).

Pathophysiology

To understand sideroblastic anemia, recall the heme synthesis pathway:

1. Glycine + Succinyl-CoA → δ-ALA (by ALA synthase, in mitochondria — needs vitamin B6 as cofactor). Rate-limiting step.
2. δ-ALA → Porphobilinogen (by ALA dehydratase, in cytoplasm). Inhibited by lead.
3. Several cytoplasmic steps → Protoporphyrin IX.
4. Back to mitochondria: Protoporphyrin IX + Fe²⁺ → Heme (by ferrochelatase). Inhibited by lead.

When any of these steps fails:

• Iron is delivered to mitochondria but cannot be inserted into protoporphyrin → iron piles up around the nucleus in mitochondria → ringed sideroblast.
• Defective erythroblasts die in the marrow → ineffective erythropoiesis.
• Body senses anemia → ↑ intestinal iron absorption (hepcidin suppressed) → progressive iron overload (hemosiderosis).

Clinical Features

Symptoms depend on the cause, the severity of anemia, and the iron overload.

General anemia symptoms

• Fatigue, weakness, pallor.
• Dyspnea on exertion, palpitations.
• Dizziness, headache.

Features of iron overload (in chronic/long-standing cases)

• Skin pigmentation (bronze).
• Hepatomegaly, liver dysfunction.
• Diabetes mellitus, hypogonadism.
• Cardiomyopathy, arrhythmias.
• (Picture similar to secondary hemochromatosis.)

Clues to specific causes

• Lead poisoning: abdominal colic, constipation, peripheral neuropathy (wrist/foot drop in adults), encephalopathy and developmental delay in children, gingival lead line.
• Alcoholism: macrocytosis may coexist (dimorphic picture), liver disease signs.
• Isoniazid use: usually patient is on anti-TB therapy without B6 supplementation.
• MDS: elderly patient, often with pancytopenia.
• Hereditary form: young male, family history, splenomegaly may be present.

Diagnosis

Diagnosis is based on a combination of iron studies, peripheral smear, and (when needed) bone marrow biopsy.

Key concept – iron pattern: The iron studies in sideroblastic anemia are the mirror image of iron deficiency anemia.

For a side-by-side iron-study comparison across microcytic anemias, see iron studies in microcytic anemia.

Differential Diagnosis

Any microcytic anemia (MCV < 80 fL) should be approached through the 4 classic causes — remembered by "TICS": Thalassemia, Iron deficiency, Chronic disease, Sideroblastic. Iron studies are the fastest way to separate them.

For more on the IDA vs thalassemia comparison see IDA vs α-thalassemia vs β-thalassemia minor.

Management

Management depends on the underlying cause. The two main goals are: (1) correct or remove the cause, and (2) prevent/treat iron overload.

1. Treat the cause

• Hereditary (X-linked): Pyridoxine (vitamin B6) — high doses, often lifelong. Many patients respond partially.
• Alcohol-induced: stop alcohol → anemia usually reverses in weeks.
• Isoniazid-induced: add or increase pyridoxine (B6). Always co-prescribe B6 with INH to prevent this.
• Lead poisoning: remove exposure + chelation (DMSA orally, or EDTA ± dimercaprol if severe / encephalopathy).
• Copper deficiency: copper replacement (and stop excess zinc).
• MDS: supportive transfusions; consider luspatercept, erythropoietin, or hypomethylating agents (azacitidine); allogeneic stem cell transplant in selected young patients.

2. Treat iron overload

• Iron chelation (deferoxamine, deferasirox, deferiprone) if ferritin is markedly elevated or after multiple transfusions.
• Avoid iron supplementation — it worsens the overload and does NOT help (the problem is utilization, not iron lack).

3. Supportive care

• Blood transfusion for symptomatic anemia (but use sparingly to limit iron load).
• Folic acid supplementation (high cell turnover).
• Treat infections, vaccinate, and monitor end-organ damage from iron overload.

For a reminder of anti-TB drug toxicities, see anti-TB drugs: mechanisms and adverse effects.

Complications

• Secondary iron overload (hemosiderosis / hemochromatosis-like picture):
  • Liver: hepatomegaly, cirrhosis, hepatocellular carcinoma.
  • Heart: cardiomyopathy, heart failure, arrhythmias.
  • Endocrine: diabetes mellitus, hypogonadism, hypothyroidism.
  • Skin: bronze pigmentation.
• Transfusion-related complications: alloimmunization, infections, additional iron load.
• Progression to AML in patients with MDS-associated sideroblastic anemia.
• Lead-specific complications: encephalopathy, peripheral neuropathy, nephropathy, developmental delay in children.

For details on adult and pediatric lead toxicity see lead poisoning in adults and lead poisoning management.

Mnemonics

Key Points for Exams