Diagnosis and Management of Anaemia
Medical Abbreviations (Alphabetical List)
| Abbreviation | Definition | Abbreviation | Definition |
|---|---|---|---|
| ACD | Anaemia of Chronic Disease | APS | Antiphospholipid Syndrome |
| CKD | Chronic Kidney Disease | CLL | Chronic Lymphocytic Leukaemia |
| DIC | Disseminated Intravascular Coagulation | EPO | Erythropoietin |
| ESA | Erythropoiesis-Stimulating Agents | FIT | Quantitative Faecal Immunochemical Testing |
| G6PD | Glucose-6-Phosphate Dehydrogenase Deficiency | HFrEF | Heart Failure with Reduced Ejection Fraction |
| HS | Hereditary Spherocytosis | HUS | Haemolytic Uraemic Syndrome |
| IDA | Iron Deficiency Anaemia | MAHA | Microangiopathic Haemolytic Anaemia |
| NHL | Non-Hodgkin's Lymphoma | RA | Rheumatoid Arthritis |
| RBC | Red Blood Cell | SCD | Sickle Cell Disease |
| SLE | Systemic Lupus Erythematosus | TTP | Thrombotic Thrombocytopenic Purpura |
Answer (True or False)
-
False. Iron deficiency can exist without anaemia (non-anaemic iron deficiency), especially in early stages.
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False. It may be absent in coexistent marrow suppression or nutrient deficiencies.
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True. Ferritin is an acute phase reactant.
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False. Biochemical confirmation is recommended before considering the option of GI investigation.
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False. Other causes include thalassaemia and sideroblastic anaemia.
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True. Meets NICE NG12 cancer screening criteria.
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True. Particularly with coexistent iron deficiency.
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True, but rarely needed.
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False. IV iron is preferred if oral is ineffective.
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True. This constellation reflects depleted iron stores, low circulating iron, and a compensatory rise in transferrin synthesis and binding capacity. It differentiates true iron deficiency from anaemia of chronic disease, where ferritin is often normal or high and TIBC is low or normal.
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True.
Microcytosis with normal or raised ferritin and normal CRP strongly suggests a haemoglobinopathy. Haemoglobin electrophoresis is essential to detect β-thalassaemia trait or HbE. α-thalassaemia trait may require DNA analysis as Hb electrophoresis can be normal. -
True.
A rise in haemoglobin ≥10 g/L within 2–4 weeks of initiating oral iron strongly supports a diagnosis of absolute iron deficiency—even when baseline ferritin is equivocal or mildly raised in the context of inflammation.
Definition
Anaemia develops when the rate of RBC production decreases and/or the rate of RBC loss increases.
Anaemia is defined by the World Health Organization (WHO) as a haemoglobin concentration below:
- 130 g/L in adult males
- 120 g/L in non-pregnant adult females
- 110 g/L in pregnant women
Anaemia is classified by MCV/reticulocyte count/blood film:
Microcytic (MCV <80 femtolitres [fL]).
Normocytic (MCV 80-100 femtolitres [fL]); can be hyperproliferative or hypoproliferative.
Hypoproliferative (reticulocyte count <2%)
Hyperproliferative (reticulocyte count >2%)Macrocytic (MCV >100 femtolitres [fL]); can be megaloblastic or non-megaloblastic.
Megaloblastic: impaired DNA maturation causing large immature RBCs (megaloblasts) and hypersegmented neutrophils.
Non-megaloblastic: preserved DNA maturation. Megaloblasts and hypersegmented neutrophils are absent.
Prevalence
Anaemia affects over 1.8 billion individuals globally, with disproportionately high rates in children, women of childbearing age, the elderly, and those with chronic diseases. In the UK, anaemia is observed in approximately 3–5% of the general population but is more common among older adults and in ethnic minorities with inherited haemoglobinopathies.
Symptoms and Signs
Symptoms include: fatigue, pallor, dyspnoea, palpitations, and thinning hair.
Symptoms suggestive of malignancy: bone pain, bleeding, easy bruising, fevers, night sweats, or weight loss.
Signs include: lymphadenopathy, ecchymoses or petechiae, splenomegaly, glossitis, koilonychia, and angular cheilitis.
Rarely, individuals can present with neurological deficits consequent to B12 deficiency.
Functional Iron Deficiency (FID)
Functional iron deficiency (FID) occurs when iron stores are adequate but unavailable for erythropoiesis, typically due to inflammation-driven hepcidin upregulation. Hepcidin inhibits ferroportin, reducing iron absorption and trapping iron in macrophages. It is common in anaemia of chronic disease, including in CKD, malignancy, and autoimmune conditions.
Key laboratory features:
Ferritin: Normal or elevated (≥100 µg/L)
TSAT: Low (<20%)
Serum iron: Low
MCV: Usually normocytic
FID impairs response to erythropoiesis-stimulating agents (ESAs) unless iron is supplemented. IV iron is preferred, as oral iron is often ineffective due to absorption blockade. Management focuses on the underlying disease and targeted iron support when TSAT is low, even if ferritin is normal or high.
Diagnosis [MCV/reticulocyte count/blood film & Other Tests]
Additional causes (not already stated in the algorithm):
Normocytic hypoproliferative: Myeloma, ACD, CKD, hypothyroidism
Normocytic hyperproliferative: Haemolytic anaemias (SCD, HS, G6PD) and *MAHA, lymphoproliferative disorders (e.g. NHL, CLL), Lead toxicity
Macrocytic megaloblastic: Autoimmune thyroid disease, Drugs (e.g. Hydroxyurea, methotrexate, trimethoprim, COC)
MAHA is a form of non-immune haemolysis caused by mechanical destruction of red blood cells as they pass through damaged or narrowed small vessels. It is characterised by the presence of schistocytes (fragmented RBCs) on blood film, elevated LDH, low haptoglobin, and signs of haemolysis (e.g. anaemia, jaundice, reticulocytosis).
Common causes of MAHA include: TTP, HUS, DIC, Malignant Hypertension, SLE, APS, Scleroderma Renal Crisis, Mechanical Prosthetic Heart Valves.
| Test | Purpose | Interpretation / Notes |
|---|---|---|
| Full Blood Count (FBC) | Initial classification | Hb, MCV, MCH, RDW to assess microcytic, normocytic, or macrocytic anaemia |
| Reticulocyte Count | Assess marrow response | High in haemolysis or bleeding; low in marrow suppression or nutrient deficiency |
| Blood Film | Morphological clues | Target cells (thalassaemia), schistocytes (MAHA), hypersegmented neutrophils (B12/folate), blast cells (ALL, AML) |
| Iron Studies | Confirm iron status | Ferritin, serum iron, transferrin saturation, TIBC; ferritin may be falsely high in inflammation |
| Vitamin B12 and Folate | Macrocytic/megaloblastic anaemia | Anti-intrinsic factor and anti-parietal cell antibodies |
| U&Es / eGFR | Assess for CKD | CKD-related anaemia is typically normocytic with low EPO levels |
| CRP / ESR | Contextualise ACD | ACD is associated with raised CRP/ESR and falsely normal/high ferritin |
| Coeliac Serology | Identify malabsorption | Check IgA and tTG antibodies |
| Haemoglobin Electrophoresis | Screen for thalassaemia / sickle cell | Essential in microcytosis with normal ferritin |
| FIT / Endoscopy | GI blood loss assessment | Mandatory in unexplained IDA in men or postmenopausal women (NICE NG12) |
| Serum Protein Electrophoresis + BJP | Myeloma screen | Include urine Bence Jones protein for light chains |
Anaemia and diagnosing cancer (NICE NG12)
| Blood test finding | Possible cancer | Recommendation |
|---|---|---|
| Iron deficiency anaemia | Colorectal | Offer FIT test |
| Non-iron-deficiency anaemia Age ≥ 60 |
Colorectal | Offer FIT test |
|
Anaemia Upper Abdominal Pain Age ≥ 55 +/- Raised platelet count +/- Nausea or vomiting |
Oesophageal or stomach | Consider non-urgent, direct access upper gastrointestinal endoscopy |
|
Anaemia Haematuria (visible) Women Age ≥ 55 +/- Thrombocytosis +/- High blood glucose +/- Unexplained vaginal discharge |
Endometrial | Consider a direct access ultrasound scan |
Causes and Treatment of Iron Deficiency Anaemia (IDA)
Diagnosing IDA
| Serum markers | Diagnosis for IDA |
|---|---|
| Haemoglobin |
<130 g/L males <120 g/L females <110 g/L in pregnancy |
| Ferritin * |
<30 µg/L if no inflammation <100 µg/L if inflammation |
| Transferrin † | Raised |
| Total iron binding capacity | Raised |
| Iron | Reduced |
| Transferrin saturations | <20% |
| Mean corpuscular volume | Low |
* Ferritin thresholds increase in the presence of inflammation, as ferritin is an acute phase reactant.
† Transferrin rises in iron deficiency but may be normal or reduced in chronic inflammation or liver disease.
Causes of IDA
| Category | Causes |
|---|---|
| Low Iron Intake | - Insufficient dietary iron (e.g., vegetarian or iron-poor diet) |
| Iron Malabsorption |
Gastrointestinal Conditions: - Atrophic gastritis - Coeliac disease - Inflammatory bowel disease (IBD) - Small bowel resection or bypass surgery |
|
Surgical and Medication-Related Factors: - Gastric surgery (e.g., gastrectomy, bariatric surgery) - Long-term proton pump inhibitor (PPI) use (causing hypochlorhydria) |
|
|
Other Conditions: - Chronic pancreatitis - Gallstones - Chronic kidney disease (CKD) - Heart failure (intestinal wall oedema) |
|
| Chronic Blood Loss |
Menstrual Loss: - Heavy or prolonged menstruation |
|
Gastrointestinal Bleeding: - Peptic ulcers - Colonic adenocarcinoma - Angiodysplasia - Hookworm infection |
Risk stratifying IDA using FIT testing
FIT has a sensitivity of 83%–91% for detecting CRC at a low detection threshold of 10 µg/g.
FIT testing is primarily recommended for patients under 60 years with symptoms suggestive of bowel cancer or unexplained IDA, but it should be used cautiously and in conjunction with other diagnostic tools.
Endoscopic investigation remains the gold standard for evaluating IDA in most cases.
Treatment
Oral ferrous sulphate remains first-line (65 mg elemental iron is equivalent to 200mg ferrous sulphate), preferably once daily or on alternate days, to minimise side-effects (e.g. constipation).
Treatment should continue for 3 months beyond normalisation of haemoglobin to replenish stores, particularly in patients with chronic disease or ongoing blood loss.
Consider intravenous iron in CKD, IBD, HFrEF (LVEF<40%) or intolerance to oral iron.
Criteria for Iron Deficiency in HFrEF:
Ferritin <100 μg/L, or
Ferritin 100–299 μg/L with transferrin saturation (TSAT) <20%
Anaemia is not required to initiate IV iron in HFrEF.
Vitamin B12 and Folate Deficiency Anaemia
Vitamin B12 and Folate, are essential co-factors in DNA synthesis, being obtained only from the diet or by supplementation, and cause macrocytic megaloblastic anaemia.
Vitamin B12 deficiency produces neurological disorders.
Causes of B12 and folate deficiency:
Low intake: chronic malnutrition, alcohol misuse, vegan diets
Malabsorption:
Lifelong B12 replacement: Autoimmune gastritis, total gastrectomy, or complete terminal ileal resection.
Other causes: Crohn's disease, coeliac disease, bacterial overgrowth, partial gastrectomy.Medication (e.g., colchicine, proton pump inhibitors, H2-receptor antagonists, metformin)
Recreational use of nitrous oxide (causes B12 deficiency)
Pernicious Anaemia vs Autoimmune Gastritis
| Feature | Pernicious Anaemia (PA) | Autoimmune Gastritis (AIG) |
|---|---|---|
| Definition | Macrocytic anaemia due to vitamin B12 deficiency caused by intrinsic factor loss | Chronic immune-mediated gastritis affecting parietal cells in the gastric corpus and fundus |
| Pathogenesis | Autoantibodies against intrinsic factor and parietal cells → impaired B12 absorption | Autoantibodies against parietal cells → progressive mucosal atrophy and achlorhydria |
| Key Autoantibodies | Anti-intrinsic factor (specific), anti-parietal cell (sensitive) | Anti-parietal cell antibodies (frequent) |
| Gastric Involvement | Indirect effect via intrinsic factor deficiency | Corpus and fundus (spares the antrum) |
| Histology | Glandular atrophy, intestinal metaplasia, lymphocytic infiltration | Parietal cell loss, metaplasia, ECL cell hyperplasia |
| Clinical Features | Macrocytic anaemia, neurological symptoms, glossitis, fatigue | Often asymptomatic; may present with iron deficiency and fatigue |
| Lab Findings | Low B12, ↑ methylmalonic acid & homocysteine, + IF antibodies | Possible B12 deficiency, ↑ gastrin, + parietal cell antibodies |
| Cancer Risk | ↑ Risk of gastric adenocarcinoma and type I carcinoid | Same as PA due to mucosal atrophy and ECL hyperplasia |
| Management | IM vitamin B12 injections for life | Monitor for B12 deficiency and malignancy; manage iron or B12 deficiency if present |
Autoimmune gastritis is the underlying cause of pernicious anaemia in most cases.
PA represents the late-stage clinical manifestation of AIG when intrinsic factor production is severely impaired, resulting in vitamin B12 malabsorption.
Patients with anti-parietal cell antibodies may develop iron deficiency first (due to hypochlorhydria) and B12 deficiency years later.
Neurological symptoms of vitamin B12 deficiency
Cognitive issues: Brain fog, memory loss, delirium, or dementia.
Eyesight problems: Blurred vision, optic atrophy, or scotoma.
Neurological/mobility issues: Balance problems, falls, impaired gait, paraesthesia, or numbness.
Treatment
Vitamin B12 deficiency may require intramuscular hydroxocobalamin 1 mg every 2–3 days for 2 weeks, then every 3 months if pernicious anaemia is diagnosed.
Folate deficiency is treated with 5 mg oral folic acid daily for at least 4 months.
In malabsorptive conditions, parenteral therapy or long-term supplementation is indicated.
Combined vitamin B12 and folate deficiency
If a patient has folate deficiency, it is essential to check for and correct any co-existing vitamin B12 deficiency BEFORE giving folate. Folate is believed to exacerbate inhibition of vitamin B12-containing enzymes, thereby worsening vitamin B12-associated neuropathy and subacute combined degeneration of the spinal cord.
Anaemia in Chronic Kidney Disease (CKD)
If eGFR is above 60 ml/min/1.73 m², investigate other causes of anaemia as CKD is unlikely to be the cause.
If eGFR is between 30 and 60 ml/min/1.73 m², use clinical judgment to decide the extent of investigation.
If eGFR is below 30 ml/min/1.73 m², anaemia is often caused by CKD, but other causes should still be considered. CKD-associated anaemia is normocytic OR microcytic anaemia.
Decreased erythropoietin production, accumulation of erythropoiesis inhibitors, and secondary hyperparathyroidism all contribute.
Iron studies, inflammation markers, and reticulocyte indices guide management.
Inflammation markers, such as C-reactive protein (CRP), are also important because inflammation can affect iron metabolism and lead to functional iron deficiency, where iron stores are adequate but unavailable for erythropoiesis.NICE recommends
IV iron for ferritin <100 µg/L or transferrin saturation <20%, and
erythropoiesis-stimulating agents (ESAs) in iron-replete (i.e., ferritin ≥100 µg/L and transferrin saturation ≥20%) patients with symptomatic anaemia.
However, ESAs should not be used in the presence of absolute iron deficiency, as they are less effective without adequate iron stores.Hb targets should remain 100–120 g/L. This range is designed to balance the benefits of anaemia correction with the risks of adverse events, such as thrombotic complications, cardiovascular events, and mortality, which increase when Hb levels exceed 120 g/L.
Anaemia of Chronic Disease (ACD)
Typically a mild hypoproliferative normocytic anaemia with elevated ferritin and low transferrin saturation.
Co-existing iron deficiency produces a microcytic anaemia.
Functional iron deficiency is common due to hepcidin upregulation.
Management focuses on the underlying chronic inflammatory, infectious, auto-immune, or malignant process.
Iron or ESA therapy may be appropriate in select cases.
However, the presence of functional iron deficiency, often limits the effectiveness of ESA therapy unless corrected with iron supplementation.
Myeloma: diagnosis and management
Type of anaemia:
Myeloma typically causes normocytic hypoproliferative anaemia
Key Symptoms and Signs of Myeloma:
Bone-related symptoms: Bone pain (especially in the back or ribs), fractures, and spinal cord compression.
Renal issues: Acute or chronic kidney disease.
Infections: Increased susceptibility to infections due to immune system suppression.
Fatigue: Often caused by anemia.
Neurological symptoms: Peripheral neuropathy or symptoms related to spinal cord compression.
Other complications: Hypercalcemia (leading to nausea, confusion, or constipation).
Laboratory Investigations:
Serum protein electrophoresis and serum-free light-chain assay
Serum immunofixation: Used if serum protein electrophoresis is abnormal to confirm paraproteins.
Bone marrow aspirate and trephine biopsy: To determine plasma cell percentage (via morphology) and phenotype (via flow cytometry).
Fluorescence in-situ hybridization (FISH): To identify high-risk abnormalities (e.g., t(4;14), del(17p)) for prognosis.
Serum-free light-chain ratio: To assess prognosis.
Imaging Investigations:
Whole-body MRI: First-line imaging for suspected myeloma.
Whole-body low-dose CT: Alternative if MRI is unsuitable or declined.
FDG PET-CT: For newly diagnosed myeloma or smouldering myeloma to assess bone disease and extra-medullary plasmacytomas.
Follow-Up
Recheck Hb and indices 2–4 weeks after starting treatment. Monitor for response, adherence, and side effects. If no improvement, reassess for bleeding, malabsorption, or alternative pathology.
Chronic conditions may require long-term monitoring.
Prevention
Encourage iron-rich diets and fortified foods in at-risk groups.
Folic acid supplementation is recommended preconception and during pregnancy.
Routine screening for anaemia is advised in pregnancy, the elderly, those with CKD, and individuals on long-term medications affecting absorption.