Anaemia: Assessment ✅

Anaemia of Chronic Disease ✅

🧾 Aetiology

• Chronic inflammation diverts iron into storage sites, limiting its availability for red cell production.
• Inflammatory cytokines (especially IL-6) ↑ hepcidin → blocks ferroportin → ↓ intestinal iron absorption & ↓ iron release from macrophages → "functional iron deficiency".
• Reduced responsiveness to erythropoietin → impaired erythropoiesis.
• Additional factors: erythrophagocytosis, bone marrow infiltration by tumour or infection.

📌 Causes

• Rheumatological: Rheumatoid arthritis, SLE, PMR, vasculitis, sarcoidosis.
• Infective: TB, osteomyelitis, HIV/AIDS, chronic viral, bacterial, fungal, protozoal infections.
• Gastrointestinal: Crohn’s disease, ulcerative colitis.
• Renal: Chronic kidney disease (reduced erythropoietin production).
• Oncological: Solid tumours, haematological malignancies.
• Cardiac: Chronic heart failure, endocarditis.

🧪 Investigations

• FBC: Hb ↓ (usually normocytic/normochromic; can be microcytic), low reticulocyte count.
• Iron studies:
  • Serum iron: ↓ or normal
  • TIBC: ↓ (key discriminator from iron deficiency)
  • Ferritin: normal or ↑ (acute phase reactant)
  • Bone marrow iron: ↑ (stores present but not mobilised)
• Inflammatory markers: ESR and CRP ↑.
• Serum transferrin receptor: Normal (vs ↑ in iron deficiency anaemia).
• Zinc protoporphyrin: ↑ due to impaired haem synthesis.

⚕️ Management

• 1️⃣ Treat underlying cause: Control of infection, autoimmune disease, or malignancy often improves anaemia.
• 2️⃣ Exclude other causes: Always rule out coexistent iron deficiency anaemia.
• 3️⃣ ESAs: Erythropoiesis-stimulating agents (e.g. Epoetin alfa) in CKD or severe cases; usually combined with iron therapy.
• 4️⃣ Parenteral iron: Oral iron often ineffective (blocked absorption); IV iron can help in selected patients despite high ferritin.
• 5️⃣ Blood transfusion: Reserved for severe/symptomatic anaemia (Hb <8–9 g/dL).

🧑‍⚕️ Case Examples - Anaemia of Chronic Disease (ACD)

• Case 1 (Rheumatoid Arthritis): 🦴 A 62-year-old woman with long-standing rheumatoid arthritis presents with fatigue and pallor. Bloods show Hb 9.8 g/dL, MCV 86 fL, ferritin raised, serum iron low, and TIBC low. Diagnosis: Anaemia of chronic disease secondary to chronic inflammation. Management: Optimise RA control with DMARDs/biologics; no role for iron unless deficiency coexists. Monitor symptoms and haemoglobin.
• Case 2 (Chronic Kidney Disease): 💊 A 70-year-old man with CKD stage 4 reports increasing tiredness. FBC shows normocytic anaemia (Hb 9.5 g/dL). Ferritin is normal, transferrin saturation low, and reticulocyte count reduced. Management: Exclude concurrent iron deficiency, then initiate erythropoiesis-stimulating agent (ESA) with iron supplementation if required.
• Case 3 (Malignancy - Lung Cancer): 🎗️ A 68-year-old man with non-small cell lung cancer undergoing chemotherapy presents with fatigue and pallor. Hb 8.9 g/dL, MCV 88 fL, ferritin raised, serum iron low, CRP elevated. Diagnosis: Anaemia of chronic disease associated with malignancy and systemic inflammation. Management: Treat underlying malignancy, consider blood transfusion for symptomatic relief, and avoid unnecessary iron therapy unless true deficiency is proven.

📚 References & NICE Guidelines

• Anaemia of chronic disease: A review (2018)
• Anaemia of chronic disease – Clinical Medicine (RCP, 2013)
• NICE NG8: Chronic kidney disease: managing anaemia – Comprehensive guidelines on the use of ESAs and iron therapies in CKD-induced anaemia.
• NICE CKS: Anaemia - iron deficiency – Useful for understanding the clinical differentiation between true iron deficiency and functional iron deficiency seen in ACD.

Iron deficiency Anaemia 🩸

⚠️ Iron deficiency anaemia in an older patient = gastrointestinal malignancy until proven otherwise. 👉 In men and postmenopausal women, always investigate with upper GI endoscopy and colonoscopy unless a clear non-GI cause is identified.

📖 About

• Iron deficiency anaemia (IDA) is the commonest cause of anaemia worldwide.
• In adults, IDA should be assumed to be due to blood loss until proven otherwise.
• Gastrointestinal malignancy must always be excluded 🚨

🧬 Aetiology

• Iron deficiency arises from inadequate intake, excess loss, or increased requirement.
• Most body iron is recycled from senescent red cells; depletion occurs gradually.
• A latent iron-depleted phase precedes the development of anaemia.

🩸 Causes

• Gastrointestinal blood loss (most common in adults)
• Menstrual blood loss
• Pregnancy (↑ iron requirements)
• Dietary deficiency
• Hookworm 🪱 (most common cause worldwide)
• Schistosomiasis
• Paterson–Brown–Kelly (Plummer–Vinson) syndrome

🩺 Clinical Features

• Fatigue, pallor, reduced exercise tolerance
• Exertional breathlessness
• Koilonychia – spoon-shaped nails
• Pallor of conjunctiva and palmar creases
• Brittle nails, hair loss, cheilosis, glossitis
• Flow murmurs (high-output state)
• Pica – craving ice (pagophagia) or clay (geophagia)

🔎 Investigations

• Microcytic, hypochromic anaemia (↓ MCV, ↓ MCH)
• Low reticulocyte count (reduced marrow response)
• Low serum ferritin (best single marker unless inflammation present)
• Plasma iron ↓, total iron-binding capacity (TIBC) ↑
• Transferrin saturation < 15% → impaired haemoglobin synthesis
• Soluble transferrin receptor ↑ (useful in inflammatory states)

📊 Key Components of Iron Studies

• Serum Iron: 10–30 µmol/L
• TIBC: 45–70 µmol/L
• Transferrin Saturation: 20–50%
• Ferritin: 15–300 micrograms/L (men), 15–200 micrograms/L (women)

🧾 Interpreting Iron Studies

Patterns of iron studies help distinguish iron deficiency from inflammatory and overload states.

🧪 Additional Investigations

• PR exam ± proctoscopy
• Upper GI endoscopy ± duodenal biopsy (coeliac disease)
• Colonoscopy (polyps, malignancy, colitis)
• Coeliac serology (anti-tTG, EMA)
• Urinalysis (haematuria)
• Capsule endoscopy / small bowel imaging for obscure bleeding

💊 Oral iron: Once-daily or alternate-day dosing is sufficient.
❌ Multiple daily dosing increases side effects without improving absorption.

💊 Management

• Identify and treat the underlying cause.
• Oral iron: Ferrous sulfate 200 mg once daily or alternate days for ≥3 months after Hb normalises.
• IV iron: Indicated if oral iron is not tolerated, malabsorbed, ineffective, or when rapid repletion is required.
• Blood transfusion: Reserved for severe or symptomatic anaemia or haemodynamic compromise.

🩸 Important: Transfusion treats the immediate oxygen-carrying deficit but does not correct iron deficiency. ➡️ Patients transfused for iron-deficiency anaemia should usually receive iron replacement (often IV) once stable to replenish iron stores and prevent relapse.

Teaching Commentary 🩸

Iron-deficiency anaemia reflects depleted iron stores and impaired erythropoiesis. Transfused red cells contain iron, but this iron is locked within donor haemoglobin and is not immediately available to the patient’s bone marrow. Without iron replacement, haemoglobin commonly falls again once transfused cells senesce. UK guidance therefore emphasises iron therapy as definitive treatment, with transfusion reserved for acute stabilisation. Unexplained IDA in men and postmenopausal women mandates urgent gastrointestinal investigation.

📚 References (UK)

• British Society for Haematology. Identification and management of preoperative anaemia in adults. Br J Haematol. 2024.
• British Society of Gastroenterology. Guidelines for the management of iron deficiency anaemia in adults. Gut. 2021.
• NICE. Blood transfusion (NG24). 2015 (updated).
• BMJ Best Practice. Iron deficiency anaemia in adults.

Macrocytic anaemia 🩸

📖 About

• Haemoglobin is low, with MCV > 96 fl.
• Macrocytosis is the hallmark, but not all causes are megaloblastic.

🔬 Megaloblasts

• Megaloblasts = developing red cells with nuclear maturation arrested due to impaired DNA synthesis.
• Commonest causes: Vitamin B12 deficiency and Folate deficiency.
• Involves the entire haemopoietic system, not just red cells.
• B12 deficiency can exist before overt anaemia develops (neurological features may precede).

🩺 Aetiology & Causes

🔎 Investigations

• Blood counts: Low Hb, MCV >96 fl, often pancytopenia.
• Blood film: Hypersegmented neutrophils, oval macrocytes.
• LDH ↑ markedly (due to ineffective erythropoiesis).
• Reticulocyte count ↓ (underproduction).
• Serum B12 & Folate: to distinguish the cause.
• Bone marrow: Megaloblasts (if unclear diagnosis).

💊 Management

• Treat the underlying cause (e.g., dietary deficiency, malabsorption, pernicious anaemia).
• Always replace B12 before (or with) folate if both are low → prevents neurological complications.
• B12 replacement: Hydroxocobalamin IM injections (NICE: 1 mg IM alternate days × 2 weeks, then every 3 months for life in pernicious anaemia).
• Folate replacement: Folic acid 5 mg daily (after ruling out isolated B12 deficiency).
• Monitor Hb, reticulocyte response, and symptoms.

Cases - Macrocytic Anaemia

• Case 1 - Vitamin B12 Deficiency (Pernicious Anaemia): A 65-year-old woman presents with tiredness, glossitis, and numbness in her feet. FBC: Hb 8.5 g/dL, MCV 112 fL. Peripheral smear: macro-ovalocytes and hypersegmented neutrophils. Serum B12 low, intrinsic factor antibodies positive. Diagnosis: Macrocytic anaemia due to pernicious anaemia.
• Case 2 - Folate Deficiency (Dietary): A 25-year-old man with a history of alcohol misuse presents with pallor and mild jaundice. FBC: Hb 9.2 g/dL, MCV 118 fL. Serum folate low, B12 normal. Diagnosis: Macrocytic anaemia from folate deficiency, likely nutritional/alcohol related.
• Case 3 - Alcohol and Liver Disease: A 50-year-old man with chronic liver cirrhosis presents with fatigue. FBC: Hb 10.0 g/dL, MCV 110 fL. Blood film: target cells and macrocytes. LFTs abnormal. Diagnosis: Macrocytic anaemia due to alcohol-related liver disease.
• Case 4 - Myelodysplastic Syndrome (MDS): A 72-year-old man presents with anaemia and recurrent infections. FBC: Hb 8.9 g/dL, MCV 105 fL, neutropenia, thrombocytopenia. Blood film: dysplastic changes. Bone marrow: hypercellularity with dysplastic precursors. Diagnosis: Macrocytic anaemia as part of MDS.
• Case 5 - Drug-Induced (Methotrexate): A 58-year-old woman with rheumatoid arthritis on methotrexate presents with fatigue. Hb 9.4 g/dL, MCV 108 fL. Folate levels reduced. Diagnosis: Macrocytic anaemia secondary to folate antagonism (methotrexate).

Teaching Commentary 📘

Macrocytosis is defined as MCV >100 fL. Causes can be divided into megaloblastic (B12 or folate deficiency impairing DNA synthesis) and non-megaloblastic (alcohol, liver disease, hypothyroidism, drugs, MDS). Blood film clues: hypersegmented neutrophils in megaloblastic anaemia; target cells in liver disease; dysplasia in MDS. Always check B12 before starting folate replacement, as unopposed folate can worsen neurological deficits. Management focuses on cause: lifelong B12 injections in pernicious anaemia, folate replacement in deficiency, alcohol cessation, or disease-specific therapy (e.g., MDS supportive/transplant).

Megaloblastic anaemia 🩸

📖 About

• Macrocytic anaemia is most often due to Folate or Vitamin B12 (cobalamin) deficiency.
• This impairs normal DNA synthesis, leading to ineffective cell division.
• Results in ineffective erythropoiesis with destruction of immature precursors in bone marrow.

🧬 Aetiology / Pathophysiology

• Failure of Homocysteine → Methionine conversion (needs Folate + B12 as cofactors).
• B12 also required for Methylmalonyl-CoA → Succinyl-CoA; hence ↑ methylmalonic acid is specific for B12 deficiency.
• Arrested nuclear maturation → large cells (macrocytosis) with open chromatin.
• Pancytopenia may occur: red cells, white cells, and platelets all reduced.

⚠️ Causes

• B12 deficiency: Pernicious anaemia (anti-IF Ab), gastrectomy, ileal disease (Crohn’s, ileal resection), vegan diet, nitrous oxide abuse.
• Folate deficiency: Poor diet, alcoholism, increased demand (pregnancy, haemolysis), malabsorption (coeliac disease).
• Drugs: Methotrexate, Azathioprine, Hydroxyurea, phenytoin, antiretrovirals, chemotherapy.
• Bone marrow disorders: Myelodysplastic syndrome.

🩺 Clinical Features

• General: Fatigue, pallor, exertional breathlessness.
• Mucocutaneous: Angular stomatitis, glossitis (“beefy tongue”).
• Skin: Premature greying, vitiligo.
• Neurology (B12 deficiency): Peripheral neuropathy, impaired vibration/position sense, ataxia, subacute combined degeneration (posterior + lateral columns). ⚡ These may precede anaemia.

🔎 Investigations

• FBC: Low Hb, raised MCV, ± low platelets/WCC.
• Blood film: Hypersegmented neutrophils (≥6 lobes), oval macrocytes.
• Haemolysis markers: ↑ LDH, ↑ bilirubin.
• Reticulocytes: Low (underproduction).
• Confirmatory tests: Serum B12 & Folate; methylmalonic acid ↑ in B12 deficiency only.
• Pernicious anaemia screen: Anti-intrinsic factor antibodies (NICE).

💊 Management

• Replace both B12 and Folate if unsure (folate alone in B12 deficiency can worsen neurological injury).
• B12 replacement: Hydroxocobalamin 1 mg IM:
  • No neurological signs → 3× weekly for 2 weeks, then every 3 months lifelong if cause persists.
  • With neurological signs → alternate days until no further improvement, then every 2 months.
• Folate replacement: Folic acid 5 mg PO daily for ≥4 months, but only after B12 repletion confirmed.
• Address cause: dietary advice, treat malabsorption, stop causative drugs, manage MDS if present.

📚 References

• NICE CKS – Anaemia, B12 and Folate Deficiency
• UpToDate – Megaloblastic Anaemias

Cases - Megaloblastic Anaemia

• Case 1 - Pernicious Anaemia (Vitamin B12 Deficiency): A 68-year-old woman presents with fatigue, glossitis, and paraesthesia in her feet. FBC: Hb 8.6 g/dL, MCV 115 fL. Blood film: macro-ovalocytes and hypersegmented neutrophils. Serum B12 low, intrinsic factor antibodies positive. Diagnosis: Megaloblastic anaemia due to pernicious anaemia.
• Case 2 - Folate Deficiency in Pregnancy: A 26-year-old woman at 20 weeks gestation complains of tiredness and shortness of breath. Hb 9.2 g/dL, MCV 112 fL, serum folate low, B12 normal. She has not been taking antenatal supplements. Diagnosis: Folate-deficient megaloblastic anaemia in pregnancy.
• Case 3 - Drug-Induced (Methotrexate): A 54-year-old man with psoriasis on methotrexate develops anaemia. FBC: Hb 9.0 g/dL, MCV 110 fL. Blood film: macrocytosis with hypersegmented neutrophils. Folate level low. Diagnosis: Megaloblastic anaemia secondary to folate antagonism from methotrexate.

Teaching Commentary 📘

Megaloblastic anaemia arises from defective DNA synthesis in erythroid precursors, usually due to vitamin B12 or folate deficiency. Classic blood film findings: macro-ovalocytes and hypersegmented neutrophils. - B12 deficiency often causes neurological features (peripheral neuropathy, subacute combined degeneration). Common causes: pernicious anaemia, gastrectomy, vegan diet, malabsorption (Crohn’s). - Folate deficiency is common in pregnancy, alcoholism, poor diet, and with drugs (methotrexate, phenytoin). Always measure both B12 and folate; correcting folate alone in B12 deficiency risks worsening neuro symptoms. Treatment: parenteral B12 (hydroxocobalamin IM in UK) or oral folate depending on deficiency.

Microcytic anaemia 🩸

⚠️ Teaching Pearl: Once daily or alternate-day ferrous sulphate (FeSO₄) is sufficient. Please stop prescribing TDS iron - it only increases side effects without improving absorption.

📖 About

• Reduced Hb for age/sex.
• Microcytosis: red cells < 80 fl (low MCV).
• Often detected incidentally on FBC; must be explained and not dismissed.

🧬 Aetiology / Pathophysiology

• Red cell production is driven by Erythropoietin.
• If haemoglobin cannot be produced adequately, precursors undergo more divisions → smaller red cells.
• Microcytosis reflects the “limiting factor” in haem synthesis:
  • Iron deficiency → lack of iron.
  • Thalassaemia → globin chain synthesis failure.
  • Chronic disease → impaired iron mobilisation.
  • Sideroblastic → impaired incorporation of iron into haem.

⚠️ Causes of Microcytic Anaemia

• Iron Deficiency Anaemia (IDA): ↓ ferritin, ↓ serum iron, ↑ TIBC, ↓ transferrin saturation. [No iron in bone marrow]
• Thalassaemia trait: Very low MCV, normal/high ferritin, ↑ HbA2 on electrophoresis.
• Anaemia of Chronic Disease: Normal/↑ ferritin, ↓ serum iron, ↓ TIBC (iron sequestered in macrophages).
• Sideroblastic anaemia: Hypochromic cells, ↑ iron in marrow, ring sideroblasts on staining.
• Toxicity: Lead or aluminium poisoning.

🩺 Clinical Features

• General: Fatigue, weakness, exertional dyspnoea.
• Skin/nails: Koilonychia (spoon nails), brittle nails, pallor.
• Mucosa: Glossitis, angular cheilitis.
• Cardiac: Flow murmurs in severe anaemia.
• Clues to cause: Menstrual loss, NSAID/aspirin use, GI symptoms, ethnicity (thalassaemia risk).

🔎 Investigations

• FBC: Microcytosis, hypochromia, anisopoikilocytosis.
• Iron studies:
  • IDA → ↓ ferritin, ↓ serum iron, ↑ TIBC, ↓ transferrin saturation.
  • ACD → ↑ ferritin, ↓ serum iron, ↓ TIBC.
• Raised soluble transferrin receptors (newer marker for IDA).
• Blood film: Hypochromic microcytes.
• Bone marrow: Erythroid hyperplasia ± absent iron stores.
• Identify bleeding source: OGD, colonoscopy, small bowel studies, technetium-labelled RBC scan.
• Other: Pelvic USS for gynae blood loss, Hb electrophoresis for thalassaemia.

🌍 Causes of Iron Deficiency Anaemia

• Blood loss: GI tract (ulcer, cancer, angiodysplasia), urinary tract, epistaxis, hookworm (worldwide commonest).
• Physiological: Pregnancy, growth spurts.
• Increased demand: Adolescence, chronic illness.
• Malabsorption: Coeliac disease, post-gastrectomy.
• Poor intake: Malnutrition, restrictive diets.

💊 Management

• Always identify and investigate cause → especially upper and lower GI endoscopy in older patients (GI cancer until proven otherwise).
• Iron replacement: Ferrous sulphate 200 mg OD or alternate days × 3–6 months. Monitor Hb rise (1 g/dL per week expected).
• IV iron if intolerant to oral or need rapid replenishment.
• Other: Chelation therapy if lead toxicity, pyridoxine may help sideroblastic anaemia.
• Transfusion only if severe/symptomatic or ongoing blood loss.

Cases - Microcytic Anaemia (5 Examples)

• Case 1 - Iron Deficiency Anaemia (IDA): A 42-year-old woman presents with fatigue, pica, and brittle nails. She has heavy menstrual bleeding. Hb 8.9 g/dL, MCV 68 fL, ferritin 7 micrograms/L. Blood film shows hypochromic microcytes. Diagnosis: IDA secondary to menorrhagia.
• Case 2 - β-Thalassaemia Trait: A 25-year-old man of Mediterranean origin is found to have microcytosis on routine testing (Hb 12 g/dL, MCV 62 fL). Ferritin is normal. Hb electrophoresis shows HbA₂ 5.5%. Blood film: target cells. Diagnosis: β-thalassaemia minor (carrier state).
• Case 3 - Anaemia of Chronic Disease (ACD): A 70-year-old man with long-standing rheumatoid arthritis develops mild anaemia. Hb 10.5 g/dL, MCV 78 fL. Iron low, ferritin high, TIBC low. Blood film: normochromic–microcytic picture. Diagnosis: ACD due to chronic inflammation.
• Case 4 - Sideroblastic Anaemia (Alcohol-Related): A 60-year-old man with heavy alcohol use presents with pallor and fatigue. Hb 9.2 g/dL, MCV 72 fL. Iron and ferritin raised. Bone marrow aspirate: ring sideroblasts. Diagnosis: Acquired sideroblastic anaemia from alcohol toxicity.
• Case 5 - Lead Poisoning: A 12-year-old boy living in an old house presents with abdominal pain, learning difficulties, and anaemia. Hb 8.0 g/dL, MCV 74 fL. Blood film: basophilic stippling. Serum lead level high. Diagnosis: Microcytic anaemia due to lead poisoning.

Teaching Commentary 🧾

These cases illustrate the five classic causes of microcytosis: - IDA: Low ferritin, high TIBC, hypochromic film. - Thalassaemia: Marked microcytosis, normal iron, raised HbA₂, target cells. - ACD: Low iron, low TIBC, normal/high ferritin. - Sideroblastic: High iron, abnormal ring sideroblasts, often alcohol/drug related. - Lead poisoning: Basophilic stippling, neurological/GI symptoms. In exams, pattern recognition (iron studies + blood film) is crucial to distinguishing between them.