Reduction in cell counts - anaemia
Description
- Hb or red cell mass below the reference range for age, sex, ethnicity and altitude
- WHO: Hb <130 g/L (men), <120 g/L (non-pregnant women), <110 g/L (pregnancy)
- Anaemia is a finding, never a diagnosis - the work is finding the cause
Two orthogonal classifiers - use both
- MCV -> microcytic / normocytic / macrocytic
- Reticulocyte count -> production failure (low) vs loss or destruction (high)
| Low retics | High retics | |
|---|---|---|
| Micro | Iron deficiency, ACD, sideroblastic | Thalassaemia (retics inappropriately low for haemolysis) |
| Normo | ACD, CKD, marrow failure/infiltration, early iron deficiency | Acute bleeding, haemolysis |
| Macro | B12/folate, MDS, alcohol, liver, hypothyroid, drugs | Haemolysis with brisk reticulocytosis |
- Spurious anaemia: pregnancy and over-transfusion dilute; a raised MCV can be artefact from cold agglutinins, an old sample, hyperglycaemia or leucocytosis**
Epidemiology
- ~1/4 of the world's population; iron deficiency is the commonest single cause worldwide
- Australia: ~8% of women of reproductive age; ~20% have depleted iron stores (ferritin <30 microg/L)
- Prevalence rises steeply after age 65 - anaemia in an older person is never "age-related", it has a cause
- ~1/3 of hospital inpatients anaemic on admission
Aetiopathogenesis
Compensation
- inc cardiac output (dec viscosity, dec afterload)
- inc tissue O2 extraction
- Shunting to brain and myocardium
- inc 2,3-DPG -> right shift of the O2 dissociation curve -> more unloading
- inc erythropoietin -> reticulocytosis (takes 3-5 days - a normal retic count on day 1 of a bleed means nothing)
Microcytic
- Iron deficiency - commonest
- Blood loss (GI, menstrual, urinary), malabsorption (coeliac, post-gastrectomy, atrophic gastritis, PPI, bariatric surgery), hookworm, inc demand (pregnancy, infancy)
- Thalassaemia - see separate note
- Anaemia of chronic disease - microcytic only when longstanding
- Sideroblastic - congenital (ALAS2, X-linked), or acquired: alcohol, lead, isoniazid, chloramphenicol, copper deficiency, zinc excess, MDS with ring sideroblasts (SF3B1)
Normocytic
- Anaemia of chronic disease/inflammation - hepcidin driven: inc hepcidin -> internalises ferroportin -> iron trapped in macrophages + dec gut absorption; plus blunted EPO response and shortened RBC survival
- CKD - EPO deficiency
- Acute blood loss, hypersplenism, early iron deficiency
- Haemolysis, marrow failure or infiltration, endocrine (hypothyroid, hypoadrenal, hypopituitary)
Macrocytic
- Megaloblastic - impaired DNA synthesis; nuclear:cytoplasmic asynchrony affects all three lineages, so pancytopenia is common
- B12: pernicious anaemia, gastrectomy, terminal ileal disease/resection, bacterial overgrowth, fish tapeworm, vegan diet, metformin, nitrous oxide
- Folate: poor intake, alcohol, malabsorption, inc turnover (pregnancy, haemolysis, malignancy, dialysis)
- Drugs: methotrexate, trimethoprim, pentamidine, phenytoin, hydroxyurea, azathioprine, mercaptopurine, cytarabine, fluorouracil, zidovudine, thioguanine, cyclophosphamide
- Non-megaloblastic - alcohol, liver disease, reticulocytosis, hypothyroidism, MDS, myeloma, aplastic anaemia, copper deficiency, arsenic, Down syndrome
Diagnosis
Clinical
- Early: pallor, fatigue, irritability, dec exercise tolerance, sleepiness
- Severe: weakness, exertional dyspnoea, flow murmur, angina, high-output cardiac failure
- Symptoms track the rate of fall, not the absolute Hb - chronic Hb 60 can be ambulant
Pointers on examination
- Koilonychia, angular cheilitis, glossitis -> iron deficiency
- Jaundice + splenomegaly -> haemolysis
- Subacute combined degeneration, dorsal column loss, lemon-yellow tinge -> B12
- Lymphadenopathy, bone pain, purpura -> malignancy or marrow failure
Sequence
1. FBE + film + reticulocyte count - always request the film
2. Iron studies, B12, folate, UEC, LFT, TSH, CRP
3. Haemolysis screen if retics high: LDH, bilirubin, haptoglobin, DAT
4. Bone marrow if unexplained, or with abnormal cells, pancytopenia, or a paraprotein
Interpreting iron studies
| Iron deficiency | ACD | Combined | |
|---|---|---|---|
| Ferritin | dec (<30) | Normal/inc | Low-normal |
| Transferrin/TIBC | inc | dec | Variable |
| Transferrin saturation | dec (<15-20%) | dec | dec |
| Soluble transferrin receptor | inc | Normal | inc |
- Ferritin is an acute phase reactant - a ferritin of 100 does not exclude deficiency if CRP is raised (use <100 as the cutoff in inflammation, CKD or heart failure)
- *Iron deficiency in a man or a post-menopausal woman is a GI malignancy until proven otherwise - gastroscopy and colonoscopy*
- Also test for coeliac disease and H. pylori
Film clues
| Finding | Suggests |
|---|---|
| Hypersegmented neutrophils | B12/folate deficiency |
| Target cells | Thalassaemia, liver disease, post-splenectomy |
| Basophilic stippling | Thalassaemia, lead poisoning, sideroblastic |
| Spherocytes | Hereditary spherocytosis, warm AIHA |
| Schistocytes | MAHA - TTP, HUS, DIC, mechanical valve |
| Bite cells / blister cells | G6PD |
| Rouleaux | Myeloma, high ESR states |
| Leucoerythroblastic | Marrow infiltration, myelofibrosis |
| Howell-Jolly bodies | Hyposplenism |
| Pencil cells | Iron deficiency |
Management
*Treat the cause, not the number.*
A. Iron deficiency
- Oral iron: ~100 mg elemental iron, alternate days (daily dosing raises hepcidin and absorbs less - alternate-day dosing absorbs more, with fewer side effects)
- Take with vitamin C, away from food, tea, calcium, PPIs
- Response: reticulocytosis by day 5-7, Hb rise ~20 g/L per 3-4 weeks
- Continue 3 months after Hb normalises to refill stores
- IV iron (ferric carboxymaltose, iron polymaltose) if: intolerance, malabsorption, ongoing loss exceeding oral replacement, CKD, IBD, pre-operative, second/third trimester, or need for rapid correction
- Transient hypophosphataemia (ferric carboxymaltose, via FGF23), skin staining at extravasation, infusion reactions
- Failure to respond -> non-adherence, ongoing bleeding, wrong diagnosis, malabsorption, or concurrent inflammation
B. B12 and folate
- B12: IM hydroxocobalamin loading then 3-monthly; oral high-dose only if dietary and absorption intact
- *Give B12 before or with folate* - folate alone in B12 deficiency can precipitate/worsen subacute combined degeneration
- Monitor K+ in the first days of repletion (brisk erythropoiesis -> hypokalaemia)
- Folate 5 mg daily
C. Anaemia of chronic disease
- Treat the underlying disease
- ESAs where evidence supports (CKD, some chemotherapy-induced anaemia) - target Hb 100-115 g/L, not normal; overshooting increases stroke, VTE and mortality
- Correct absolute or functional iron deficiency first - ESAs do not work in an iron-deficient patient
D. Transfusion
- Restrictive threshold: transfuse at Hb <70 g/L in stable non-bleeding adults; <80 g/L with acute coronary syndrome or cardiac surgery
- One unit at a time, then reassess - each unit raises Hb ~10 g/L
- *Transfusion is not a treatment for iron or B12 deficiency* - it treats symptoms and haemodynamic compromise
- Patient blood management: minimise iatrogenic loss, optimise preoperatively, treat coagulopathy
Associations
- Iron deficiency: coeliac disease, H. pylori, GI malignancy, hookworm, menorrhagia, hereditary haemorrhagic telangiectasia, angiodysplasia (and aortic stenosis - Heyde syndrome)
- Pernicious anaemia: autoimmune thyroid disease, T1DM, vitiligo, Addison; gastric carcinoma and carcinoid risk
- CKD, heart failure, IBD, rheumatoid arthritis, malignancy - anaemia of chronic disease
- Pregnancy - physiological dilution plus true deficiency
- Restless legs, pica, hair loss - iron deficiency without anaemia
- Alcohol - macrocytosis, folate deficiency, sideroblastic change, bleeding, hypersplenism (four mechanisms at once)
Natural history & complications
- Depends entirely on cause
- Iron deficiency: fully correctable, but recurs if the source is not found
- Untreated B12 deficiency: neurological damage may be irreversible even after haematological correction
- Neurological disease can occur with a normal MCV and normal Hb
- Anaemia is an independent predictor of mortality, hospitalisation and functional decline in heart failure, CKD and the elderly
- Severe chronic anaemia -> high-output failure, LVH, growth failure in children
- Unexplained anaemia in the elderly - a third have no identified cause after full workup; a proportion later declares as MDS
- Recheck rather than close the file
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