Anaemia — Classification and Approach

Medicine — Anaemia, NMC MBBS licence examination syllabus (Nepal Medical Council).

Anaemia: a finding, never a diagnosis

Correcting the haemoglobin without finding the cause is how a cancer gets missed.

Anaemia is one of the commonest abnormalities in medicine, and one of the most consistently mishandled. The temptation is obvious: the haemoglobin is low, iron is cheap, prescribe it and move on. The number improves, the patient feels better, and everyone is satisfied.

But anaemia is a consequence. Something is causing it — blood being lost, cells being destroyed, or a marrow that cannot keep up — and the whole clinical value of finding it lies in what it points to. An iron-deficient 68-year-old man does not have a problem with iron. He has a problem somewhere in his gastrointestinal tract, and the anaemia is how it announced itself.

🩺 Where this lives: The single most consequential rule in this chapter is that iron deficiency in a man or a postmenopausal woman means occult gastrointestinal bleeding until proven otherwise. These patients need their gut investigated, not simply their iron replaced. A colorectal cancer that bleeds a few millilitres a day produces no visible blood, no pain and no change in bowel habit for a long time — an iron-deficiency anaemia is frequently its first and only sign, and treating that anaemia in isolation removes the only clue.

Two questions answer most of it

The order matters. The MCV tells you what kind of process this is; the reticulocyte count tells you whether the marrow is responding or failing. Together they narrow almost any anaemia to a short differential before a single specialised test is ordered — and both come from tests you already have.

WHY THE MCV SPLITS THE WAY IT DOES A red cell divides until it has ENOUGH HAEMOGLOBIN. Too little haemoglobin (iron, or globin chains) → the cell divides an extra time chasing a target it cannot reach → SMALL cells → MICROCYTIC Impaired DNA synthesis (B12, folate) → the nucleus cannot keep pace with the cytoplasm → the cell grows but divides late → LARGE cells → MACROCYTIC, and MEGALOBLASTIC on the marrow Loss or destruction of NORMAL cells → the cells that remain are normal-sized → NORMOCYTIC So the index is not arbitrary. It is reporting which step of red cell production went wrong.

Presentation

SYMPTOMS — from reduced oxygen delivery Fatigue · breathlessness on exertion · palpitations Dizziness · headache · reduced exercise tolerance Angina in a patient with coronary disease SEVERITY DEPENDS ON SPEED, NOT ONLY ON THE NUMBER A haemoglobin of 70 that fell over months may be remarkably well tolerated — the body adapts. The same figure reached in hours from bleeding is an emergency. SIGNS Pallor — conjunctival and palmar creases are more reliable than skin colour Tachycardia · flow murmur · signs of heart failure KOILONYCHIA and angular stomatitis — iron deficiency GLOSSITIS — B12 or folate JAUNDICE and splenomegaly — haemolysis Neurological signs — B12

Microcytic anaemia

💡 Exam angle: ferritin is an acute phase protein, and this is asked constantly. It rises with inflammation, infection and malignancy — so an iron-deficient patient with concurrent inflammation can have a ferritin that reads normal. A low ferritin is diagnostic of iron deficiency; a normal one does not exclude it. When the picture is unclear, transferrin saturation, the blood film, or a trial of iron with reassessment resolves it.

TREATING IRON DEFICIENCY ORAL IRON is first line — effective, cheap and safe. Absorption improves with vitamin C and on an empty stomach; it is reduced by tea, calcium and antacids. GI side effects are common and cause many patients to stop; alternate-day dosing is often better tolerated and absorbed. EXPECTED RESPONSE — worth knowing, because it confirms the diagnosis: Reticulocytes rise within about a week Haemoglobin rises by roughly 10 g/L every 1–2 weeks CONTINUE for about 3 months after normalisation to refill the stores FAILURE TO RESPOND means one of four things: not taking it · not absorbing it · still bleeding · the diagnosis is wrong Do not transfuse for a number alone. Transfusion is for haemodynamic compromise or symptomatic severe anaemia, not for a haemoglobin that looks low.

Thalassaemia — the other microcytosis

Thalassaemia is inherited under-production of globin chains, and it matters here for a practical reason: it produces microcytosis that is easily mistaken for iron deficiency, and iron given to a thalassaemic patient does nothing useful while risking iron overload over time.

🔍 Pointers toward thalassaemia trait rather than iron deficiency

The numbers do not fitMarked microcytosis with only mild anaemia, and a red cell count that is normal or high — iron deficiency lowers the count as well as the size.

Iron studies are normalFerritin and transferrin saturation are unremarkable, which should stop an iron prescription before it starts.

BackgroundFamily history, and origin from a region where thalassaemia and haemoglobinopathies are prevalent — including South Asia.

ConfirmationHaemoglobin electrophoresis or HPLC. Beta-thalassaemia trait raises HbA₂; alpha-thalassaemia trait needs genetic testing and is often a diagnosis of exclusion.

Why it matters beyond this patientTrait is usually asymptomatic — but two carriers can have a severely affected child, which makes it a genetic counselling issue rather than merely a laboratory curiosity.

Macrocytic anaemia

💡 Exam angle: giving folate alone to a B12-deficient patient is a classic and dangerous examination scenario. Folate partially corrects the megaloblastic anaemia, so the blood count improves and everyone is reassured — while the subacute combined degeneration of the spinal cord progresses unchecked. If both may be deficient, replace B12 first or give both together. Note also that B12 deficiency can cause neurological disease with a completely normal haemoglobin.

PERNICIOUS ANAEMIA Autoimmune destruction of gastric parietal cells → no INTRINSIC FACTOR → B12 cannot be absorbed in the terminal ileum Antibodies: intrinsic factor antibodies are highly specific; parietal cell antibodies are more sensitive but less specific. Associated with other autoimmune disease — thyroid disease, type 1 diabetes, vitiligo — so look for the company it keeps. Treatment is PARENTERAL B12, because the absorptive mechanism itself is the problem. Oral replacement is ineffective in true pernicious anaemia.

Normocytic anaemia and haemolysis

USE THE RETICULOCYTE COUNT HIGH reticulocytes — the marrow is working ACUTE BLOOD LOSS note that the haemoglobin is initially NORMAL in acute haemorrhage, because whole blood is lost and dilution has not yet occurred HAEMOLYSIS LOW reticulocytes — the marrow is not producing Anaemia of chronic disease Chronic kidney disease — erythropoietin deficiency Marrow infiltration or aplasia Early combined deficiency FEATURES OF HAEMOLYSIS — the pattern to recognise ↑ RETICULOCYTES marrow compensating ↑ UNCONJUGATED BILIRUBIN and jaundice ↑ LDH released from broken cells ↓ HAPTOGLOBIN consumed binding free haemoglobin Blood film spherocytes, fragments, sickle cells — the film often names the cause DIRECT COOMBS TEST positive → IMMUNE haemolysis negative → non-immune

The direct Coombs test is the single most useful branch point in haemolysis: it separates immune causes (autoimmune, drug-induced, transfusion reaction, haemolytic disease of the newborn) from non-immune ones (membrane defects such as hereditary spherocytosis, enzyme defects such as G6PD deficiency, haemoglobinopathies, mechanical fragmentation and microangiopathy). Two entirely different investigative pathways follow from one test.

💡 Exam angle: G6PD deficiency is high-yield and pattern-recognisable — an X-linked enzyme defect where oxidative stress precipitates acute haemolysis. Triggers include fava beans, infection, and drugs such as primaquine, sulfonamides and nitrofurantoin. The film shows bite cells and Heinz bodies. Crucially, enzyme levels can be falsely normal during an acute episode, because the deficient cells have already been destroyed — retest after recovery.

Clinical reasoning: four presentations

🔍 Case 1 — the anaemia that is a warning

PresentationA 68-year-old man is tired. Hb 92 g/L, MCV 72 fL, ferritin 8 µg/L. No overt bleeding, normal bowel habit. He is started on ferrous sulphate and reviewed in three months.

TrapTreating the anaemia as the diagnosis.

ReasoningIron deficiency in a man has no physiological explanation. Occult gastrointestinal blood loss must be excluded, and a normal bowel habit does not argue against it — right-sided colonic tumours characteristically bleed silently.

AnswerReplace the iron and investigate the gastrointestinal tract with upper and lower endoscopy, plus coeliac serology. The anaemia is the presenting sign of something else.

🔍 Case 2 — the harmful correction

PresentationA 62-year-old with Hb 96 g/L and MCV 112 fL also reports numb feet and unsteadiness in the dark. Folate is low; B12 has not yet returned. Folic acid is started.

Key clueNumbness and worsening balance without visual input — dorsal column signs.

ReasoningThose are the features of subacute combined degeneration from B12 deficiency. Folate will partly correct the blood count while the cord lesion progresses, removing the haematological warning without treating the cause.

AnswerCheck B12 and replace it first, or give both together. Never give folate alone when B12 deficiency is possible.

🔍 Case 3 — the normal ferritin

PresentationA 55-year-old with rheumatoid arthritis has Hb 98 g/L, MCV 78 fL, ferritin 96 µg/L, CRP 64. A colleague concludes she is not iron deficient.

TrapReading ferritin as a pure measure of iron stores.

ReasoningFerritin is an acute phase reactant and rises with active inflammation. In a patient with a CRP of 64, a ferritin of 96 may conceal genuinely depleted stores — and the microcytosis is a clue, since anaemia of chronic disease is more often normocytic.

AnswerDo not exclude iron deficiency. Check transferrin saturation, review the film, and consider a trial of iron with reassessment. Both conditions frequently coexist.

🔍 Case 4 — the falsely normal enzyme

PresentationA 24-year-old man develops jaundice and dark urine three days after starting nitrofurantoin. Hb 78 g/L, reticulocytes high, LDH raised, haptoglobin undetectable, Coombs negative. Film shows bite cells. A G6PD level is reported as normal.

Key clueAn oxidant drug, acute haemolysis, bite cells — and an enzyme level that does not fit.

ReasoningDuring an acute haemolytic episode the most deficient cells have already been destroyed, leaving younger cells with higher enzyme activity. The assay therefore reads falsely normal at exactly the moment you want it.

AnswerStop the drug, support the patient, and repeat the G6PD assay after recovery. Provide a list of agents to avoid — this is a lifelong management issue, not a single episode.

Commonly confused

Confusion	The distinction	Why it matters
Iron deficiency vs chronic disease	Ferritin low versus normal or high; TIBC high versus low	Iron helps one and does nothing for the other.
Normal ferritin vs replete stores	Ferritin rises with inflammation	A normal value does not exclude deficiency.
Iron deficiency vs thalassaemia trait	Trait: marked microcytosis, mild anaemia, normal iron studies	Iron is useless and potentially harmful in trait.
B12 vs folate deficiency	Only B12 causes neurological disease	Folate alone lets cord degeneration progress.
Normal Hb vs no bleeding	Acute haemorrhage loses whole blood	The haemoglobin falls later, after dilution.
Coombs positive vs negative haemolysis	Immune versus non-immune mechanism	Two completely different differentials.
Normal G6PD during a crisis	Deficient cells are already destroyed	Retest after recovery or you will miss it.

Rapid revision

MUST-KNOW FACTS 1. Anaemia is a FINDING — always ask what is causing it. 2. First question: what is the MCV? 3. Second question: what is the reticulocyte count? 4. Microcytic: iron deficiency, thalassaemia, chronic disease, sideroblastic. 5. Normocytic: split by reticulocytes — losing/destroying versus not making. 6. Macrocytic: megaloblastic (B12, folate) or non-megaloblastic (alcohol, liver, thyroid, myelodysplasia). 7. A mixed deficiency can give a NORMAL MCV — look at the film. 8. Iron deficiency: ferritin LOW, TIBC HIGH. 9. Chronic disease: ferritin NORMAL or HIGH, TIBC LOW. 10. Ferritin is an ACUTE PHASE PROTEIN — a normal value excludes nothing. 11. Iron deficiency in a man or postmenopausal woman = investigate the GUT. 12. Expected iron response: reticulocytes up in a week, Hb ~10 g/L per 1–2 weeks. 13. Continue iron for ~3 months after normalisation to refill stores. 14. No response to iron: not taking, not absorbing, still bleeding, wrong diagnosis. 15. Thalassaemia trait: marked microcytosis, mild anaemia, normal iron studies. 16. B12 stores last years; folate stores last months. 17. Only B12 deficiency causes neurological disease. 18. Subacute combined degeneration can occur WITHOUT anaemia. 19. NEVER give folate alone if B12 deficiency is possible. 20. Pernicious anaemia needs PARENTERAL B12 — absorption is the problem. 21. Haemolysis: ↑retics, ↑unconjugated bilirubin, ↑LDH, ↓haptoglobin. 22. Direct Coombs separates immune from non-immune haemolysis. 23. G6PD deficiency: X-linked, oxidant triggers, bite cells and Heinz bodies. 24. G6PD assay can be falsely NORMAL during an acute episode — retest later. 25. Transfuse for compromise or severe symptoms, not for a number.

💡 Exam angle: the reliable threads are (a) iron deficiency in a man meaning gastrointestinal investigation, (b) ferritin rising with inflammation, (c) folate alone worsening B12 neurology, (d) the Coombs test dividing haemolysis, and (e) a falsely normal G6PD during a crisis. Three of the five are laboratory results that read normal or improve while the underlying disease continues — the same trap this stream keeps returning to.

Syllabus points

Anaemia as a finding rather than a diagnosis
The MCV and why it splits the way it does
The reticulocyte count: responding or failing marrow
Presentation and why speed matters more than the number
Iron deficiency versus anaemia of chronic disease
Ferritin as an acute phase protein
Finding the source of iron deficiency
Treating iron deficiency and the expected response
Thalassaemia trait and why iron is wrong for it
B12 and folate: the neurological asymmetry
Pernicious anaemia
Haemolysis, the Coombs test and G6PD deficiency

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