Sideroblastic Anaemia and Anaemia of Chronic Disease

Overview

Hypochromic anaemias other than iron deficiency: sideroblastic anaemia, thalassaemia (separate topic), anaemia of chronic disorders. Must distinguish from iron deficiency — iron therapy wrong/harmful here.

Sideroblastic anaemia

Marrow shows ring sideroblasts — iron-laden mitochondria ringing nucleus (Prussian blue +ve). Normal sideroblasts = few scattered granules, 30-50% of normoblasts, ↓/absent in iron deficiency. Siderocytes = same finding in mature RBC, normally absent, appear after splenectomy.

Classification:

• Hereditary — X-linked, defective ALA synthetase (1st haem-synthesis enzyme). Males affected, females carriers. Childhood/early adult onset.
• Acquired primary (idiopathic) — middle-aged/elderly, stem-cell level defect (↓ALA synthetase). Chromosomal abnormalities, neutropenia, thrombocytopenia common. = MDS type, ~10% → AML.
• Acquired secondary — drugs (isoniazid = classic cause, pyridoxine antagonist; also cycloserine, chloramphenicol, alkylating agents, alcohol, lead — all REVERSIBLE) · haematologic disease (myelofibrosis, PV, AML, myeloma, lymphoma, haemolytic anaemia) · misc (carcinoma, myxoedema, RA, SLE).

Labs: moderate-severe anaemia, hypochromic (micro/dimorphic), reduced indices (hereditary) or ↑MCV (acquired). Marrow: erythroid hyperplasia, macronormoblasts, ↑iron, ring sideroblasts. ↑ferritin, ↑serum iron, near-complete TIBC saturation (iron OVERLOAD pattern despite anaemia).

Rx: remove agent (secondary). No definitive Rx hereditary/idiopathic. Pyridoxine 200mg/day×2-3mo (routine, all types). Supportive transfusion.

Anaemia of chronic disorders

Very common. Secondary to chronic systemic disease, NO marrow invasion. Causes: chronic infection/inflammation (TB, abscess, osteomyelitis, SBE; RA, SLE, vasculitis, Crohn’s; malignancy) · renal disease · hypometabolic states (myxoedema, Addison’s, malnutrition, scurvy, pregnancy, liver disease).

Pathogenesis — 2 mechanisms:

1. Defective RBC production — iron stores adequate but TRAPPED (macrophage lactoferrin). Inflammatory cytokines (TNF, IFN-β from infection/tumour; IL-1, IFN-γ from RA/vasculitis) → ↑hepcidin → blocks iron transfer macrophage→marrow.
2. ↓RBC lifespan — hyperplastic mononuclear phagocyte system (esp. chronic renal disease)

Labs: mild-moderate anaemia (Hb<8 suggests extra cause), normocytic normochromic (MCHC slightly ↓), ↓reticulocytes, mild ↓RBC survival. Marrow: normal maturation but ↓stainable iron in normoblasts + ↑macrophage iron. ↓serum iron, ↓/normal TIBC (opposite iron deficiency’s high TIBC). ↑ferritin = KEY discriminator from true iron deficiency. ↑acute phase reactants (γ-globulin, C3, haptoglobin, α1-antitrypsin, fibrinogen, driven by IL-1) → ↑ESR.

Comparison table (memorise this)

Clinical relevance

This table alone separates 4 causes of hypochromic picture using just serum iron+TIBC+ferritin — workup before marrow needed. Ferritin = key iron-deficiency-vs-chronic-disease discriminator (both have ↓iron, but ferritin ↓ in true deficiency vs ↑ in chronic disease) — direct Rx implication (iron helps one, useless/harmful for others). Isoniazid→sideroblastic anaemia = prescribing-relevant, basis for co-prescribing pyridoxine with isoniazid. 10% leukaemic transformation in 1° acquired sideroblastic anaemia = why it’s classed under MDS, needs monitoring.

Overview

Hypochromic anaemias other than iron deficiency form a second group of disorders — sideroblastic anaemia, thalassaemia, and anaemia of chronic disorders — that must be distinguished from true iron deficiency, since iron replacement is useless (and in sideroblastic anaemia, potentially harmful) if given by mistake for the wrong condition. Thalassaemia is covered separately; this topic covers the remaining two.

Sideroblastic Anaemia

A group of disorders of diverse aetiology sharing one marrow finding: ringed sideroblasts — nucleated erythroid precursors with numerous large iron-laden mitochondria arranged around the nucleus, forming a partial or complete ring on Prussian blue staining. (Normal sideroblasts, by contrast, show only a few fine scattered granules of unutilised iron, comprising 30–50% of marrow normoblasts normally, reduced or absent in iron deficiency; siderocytes are the equivalent finding in mature red cells, normally absent from peripheral blood but appearing after splenectomy, when reticulocyte maturation shifts from spleen to peripheral blood.)

Classification

I. Hereditary — a rare X-linked disorder from defective δ-aminolevulinic acid (ALA) synthetase activity (the first enzyme of haem synthesis). Affected males have moderate-severe anaemia; female carriers are unaffected. Presents in childhood or early adulthood.

II. Acquired

• Primary (idiopathic/refractory) — occurs spontaneously in middle-aged/older adults; pathogenesis involves disturbed erythroid maturation at the haematopoietic stem cell level, again implicating reduced ALA synthetase activity. Marrow often shows chromosomal abnormalities, with accompanying neutropenia and thrombocytopenia (bleeding diathesis); spleen/liver normal or mildly enlarged, lymph nodes not enlarged. This form is classified as a myelodysplastic syndrome in the FAB classification and carries genuine leukaemic potential — about 10% progress to acute myeloid leukaemia.
• Secondary — drugs/chemicals/toxins (isoniazid, a pyridoxine antagonist, is the classic cause; also cycloserine, chloramphenicol, alkylating agents, alcohol, lead — all producing reversible sideroblastic anaemia that resolves on withdrawal), haematological disease (myelofibrosis, polycythaemia vera, acute leukaemia, myeloma, lymphoma, haemolytic anaemia), and miscellaneous inflammatory/neoplastic/autoimmune disease (carcinoma, myxoedema, rheumatoid arthritis, SLE).

Laboratory Findings

Moderate-to-severe anaemia; hypochromic (microcytic or dimorphic) blood picture; red cell indices reduced in hereditary disease, but MCV is often raised in acquired disease. Marrow shows erythroid hyperplasia, macronormoblastic erythropoiesis, raised iron stores, and pathognomonic ring sideroblasts. Serum ferritin raised; serum iron raised with near-complete TIBC saturation — a pattern of iron overload despite anaemia, the opposite of iron deficiency.

Treatment

Secondary disease: remove the offending agent. No definitive treatment for hereditary/idiopathic disease. Pyridoxine (200 mg/day for 2–3 months) is given routinely to all forms. Supportive transfusion as needed.

Anaemia of Chronic Disorders

A very commonly encountered anaemia, developing secondary to chronic systemic disease without marrow invasion. Causes fall into three groups: chronic infection/inflammation (tuberculosis, lung abscess, osteomyelitis, subacute bacterial endocarditis; rheumatoid arthritis, SLE, vasculitis, sarcoidosis, Crohn’s disease; disseminated malignancy), renal disease (uraemia, renal failure), and hypometabolic states (myxoedema, Addison’s disease, protein malnutrition, scurvy, pregnancy, liver disease).

Pathogenesis

Usually normocytic normochromic (sometimes mild microcytosis/hypochromia unrelated to iron deficiency); severity tracks the primary disease, and correction requires treating the underlying condition. Two mechanisms dominate:

1. Defective red cell production — storage iron is abundant, but iron availability to developing erythroid cells is subnormal. The hyperplastic mononuclear phagocyte system traps free iron (via the iron-binding protein lactoferrin), while inflammatory cytokines — TNF and IFN-β (bacterial infection, tumours) and IL-1 and IFN-γ (rheumatoid arthritis, autoimmune vasculitis) — suppress erythropoietin and upregulate hepcidin, the key iron-regulatory hormone, blocking iron transfer from macrophage stores into the marrow despite adequate stores overall.
2. Reduced red cell lifespan — a hyperplastic mononuclear phagocyte system also shortens circulating red cell survival, particularly in chronic renal disease.

Laboratory Findings

Mild-moderate anaemia (Hb <8 g/dL suggests an additional contributing deficiency); normocytic normochromic picture (MCHC slightly low even so); low reticulocyte count; mildly shortened red cell survival. Marrow shows normal erythroid maturation but reduced stainable iron in normoblasts despite increased macrophage iron — the same iron-trapping signature seen biochemically. Serum iron reduced, TIBC low-to-normal (contrast iron deficiency’s low iron with high TIBC). Serum ferritin raised — the single most distinguishing feature from true iron deficiency. Acute phase reactants (γ-globulin, C3, haptoglobin, α1-antitrypsin, fibrinogen), driven by IL-1, are also raised, accounting for the commonly elevated ESR.

Comparative Laboratory Diagnosis of Hypochromic Anaemias

Clinical Relevance

• This single table is the highest-yield element of the entire topic: four causes of a hypochromic (or hypochromic-adjacent) blood picture, separated cleanly by serum iron, TIBC, and ferritin alone — a pattern every one of these anaemias can be worked up with before bone marrow examination is even needed.
• Serum ferritin is specifically the value that separates anaemia of chronic disease from true iron deficiency when both show low serum iron — raised in chronic disease (an acute-phase reactant reflecting adequate-to-excess stores), reduced in true deficiency (reflecting genuinely depleted stores) — a distinction with direct treatment consequences, since iron therapy helps one and does nothing (or in sideroblastic anaemia, causes harmful iron overload) for the others.
• Isoniazid-induced sideroblastic anaemia is a directly prescribing-relevant fact for any patient on anti-tuberculous therapy, and is the reason pyridoxine is often co-prescribed with isoniazid in practice.
• The ~10% leukaemic transformation risk in primary acquired sideroblastic anaemia is what places it under myelodysplastic syndrome rather than as a purely benign anaemia, with direct implications for monitoring.

No Rendered Diagram for This Topic

Both conditions in this topic are best captured by the comparative laboratory table already in notes.md (serum iron/TIBC/ferritin/marrow findings across the four hypochromic anaemias) rather than a process diagram — the genuinely useful content here is a side-by-side numeric/qualitative comparison, which a table conveys more precisely than a flowchart could. The cytokine-mediated iron-trapping mechanism in anaemia of chronic disease is real but single-step in the sources (cytokines → hepcidin → blocked macrophage iron release), not a multi-stage cascade that benefits from a rendered diagram beyond the sentence already given under Pathogenesis.

Hand-draw suggestion (optional, not a rendered requirement): reproduce the comparative table by hand exactly as given — iron/TIBC/ferritin/marrow-iron/normoblast-iron/electrophoresis rows across all four conditions in columns — since correctly recalling this table under exam pressure is the actual skill being tested in this topic.