GC076 Pallor: Diagnosis Of Anaemia; Nutritional Anaemia; Anaemia Of Systemic Diseases

Anaemia = a haemoglobin concentration below the appropriate reference limit. WHO's 2024 cut-offs for adults aged 15–65 years are < 130 g/L in men and < 120 g/L in non-pregnant women; pregnancy has trimester-specific cut-offs. Age, pregnancy, altitude, smoking and the local laboratory method matter, so use the supplied reference interval in clinical work and exam stems rather than treating one number as universal. ^[8]

Why does it matter? Haemoglobin carries oxygen. Less Hb → less O₂ delivery → the body compensates (increased cardiac output, tachycardia, 2,3-DPG shift of the oxygen-dissociation curve). When compensation fails → symptoms.

Every anaemia falls into one (or more) of three categories: ^[1]

1. Decreased RBC production — the factory is broken
2. Increased RBC destruction — the product is being destroyed too fast
3. Blood loss — the product is leaking out

This is the single most important framework. When you see any anaemia question, the first thing your brain should do is sort it into one of these three bins.

Acute and severe anaemia: Shortness of breath, palpitation, dizziness or syncope, symptoms of cardiac ischaemia ^[1]

Chronic and insidious anaemia: Fatigue, decreased exercise tolerance, pale-looking ^[1]

Symptoms related to the cause: menorrhagia, passage of tarry stool, bone pain ^[1]

Why the difference? Acute blood loss can cause hypovolaemia before the Hb has equilibrated, whereas slowly progressive anaemia allows partial cardiovascular and 2,3-DPG adaptation. Symptoms still vary with age, comorbidity and rate of fall: an apparently comfortable patient with a very low Hb is not automatically safe. Transfusion is guided by symptoms and context; for most haemodynamically stable adult inpatients, a restrictive strategy considers transfusion below about 7 g/dL, with higher thresholds in selected cardiac/orthopaedic or cardiovascular settings. ^[12]

Physical examination findings and what they suggest: ^[1]

Physical Finding	Suggests
Features of uraemia or fluid overload	Advanced kidney disease (anaemia is usually multifactorial)
Jaundice	Haemolysis
Glossitis ± neurological signs	Vitamin B12/folate deficiency (early greying is non-specific)
Shock / tachycardia	Acute blood loss
Isolated splenomegaly	Hypersplenism
Lymphadenopathy + hepatosplenomegaly	Haematological malignancy
Abnormal abdominal mass	Carcinoma

Additional examination findings from supporting sources: ^[2]

• Koilonychia (spoon-shaped nails) → severe iron deficiency anaemia (rarely seen today)
• Conjunctival pallor → supports moderate/severe anaemia but cannot replace a haemoglobin measurement
• Pallor of palmar creases → unreliable sign but often mentioned
• Angular cheilitis → iron or B12 deficiency
• Glossitis (beefy-red tongue) → B12 / folate deficiency
• Petechiae / purpura → if concurrent thrombocytopenia (consider aplastic anaemia, leukaemia, or megaloblastic anaemia with pancytopenia)

Causes of decreased RBC production: ^[1]

• Nutritional: Iron, B12, folate deficiency
• Bone marrow disorders: Aplastic anaemia, pure red cell aplasia, neoplastic diseases
• Bone marrow suppression: Drugs, chemotherapy, irradiation
• Reduced trophic hormones: Erythropoietin (renal failure), thyroid hormone (hypothyroidism)
• Anaemia of chronic disease

Intrinsic RBC defects: ^[1]

• Enzyme deficiencies (e.g. G6PD deficiency)
• Haemoglobin defects (e.g. thalassaemias, haemoglobinopathies)
• Membrane defects (e.g. hereditary spherocytosis, elliptocytosis)

Extrinsic RBC defects: ^[1]

• Liver disease and hypersplenism
• Infections (e.g. malaria)
• Autoimmune haemolytic anaemia (warm- or cold-reacting, drug-induced)
• Microangiopathy (e.g. prosthetic valve leak, TTP, DIC)
• Transfusion reactions (e.g. ABO incompatibility)

Sites: Gastrointestinal tract, genital tract, soft tissue ^[1]

Key numbers: ^[1]

• Total body iron: ~3–4 grams (2 g in Hb, 1 g in stores)
• Daily intake: ~1 mg absorbed
• Daily loss: ~1 mg (via desquamated cells, minor GI loss)
• 2 grams in circulating RBC haemoglobin
• 1 gram in stores (ferritin, haemosiderin in macrophages/liver)

The key concept is that iron is recycled — senescent RBCs are phagocytosed by macrophages, iron is released and loaded onto transferrin, which delivers it to erythroid precursors for new haemoglobin synthesis. Basal absorption and loss are each roughly 1 mg/day in many adults, although absorption can rise when stores are depleted. This is why chronic blood loss is such an important adult cause: each millilitre of blood contains about 0.5 mg iron, so ongoing losses can outrun replacement.

Reading the two recycling diagrams: the tiny dietary/loss arrows (~1 mg/day) sit beside the much larger internal flux between circulating RBCs, macrophages and marrow. Diferric transferrin binds transferrin receptor 1 on an erythroblast and is endocytosed; acidification releases iron, while apotransferrin and its receptor recycle to the surface. Iron is delivered largely to mitochondria for haem synthesis, combined with globin, and packaged into new RBCs. After roughly 120 days, macrophages clear senescent RBCs and return iron through ferroportin to transferrin. Therefore, blocking macrophage export can restrict erythropoiesis even when total-body stores are ample.

Non-haem iron absorption is favoured by: ^[1]

• Gastric processing and an acidic environment, which improve solubility and release of food-bound iron
• Conditions that impair absorption:
  • Gastrectomy
  • Prolonged PPI use
  • Autoimmune gastritis
• Once absorbed, iron binds to transferrin for transport

What the diagram shows: luminal ferric iron is reduced by duodenal cytochrome B (DCYTB) and ferrous iron enters via DMT1. Gastric acid improves availability, but achlorhydria does not make all absorption impossible; long-term PPI exposure is a risk factor to assess in context rather than proof of causation.

Detailed iron transport across the duodenal mucosa (from lecture diagram): ^[1]

1. Lumen → enterocyte: Fe³⁺ reduced to Fe²⁺ by DCYTB → Fe²⁺ enters via DMT1 (a separate putative heme transporter handles heme iron)
2. Inside enterocyte: Fe²⁺ is either stored as ferritin or exported
3. Enterocyte → plasma: Fe²⁺ exported via ferroportin → oxidised to Fe³⁺ by hephaestin → Fe³⁺ binds transferrin
4. Hepcidin acts at ferroportin on the basolateral surface, blocking iron export when hepcidin is elevated

Lecture MCQ answer: chronic blood loss ^[1]

This is the key answer in the deck's adult clinical context, especially for an adult man or postmenopausal woman. Population-wide causes vary with age, menstruation, pregnancy, diet and parasites. The logic remains important: because the iron cycle is nearly closed, persistent occult GI loss or heavy menstrual bleeding progressively depletes stores.

Common causes by system:

• GI tract: Peptic ulcer, gastritis (including NSAID-induced), colorectal carcinoma, angiodysplasia, oesophageal varices, hookworm
• Genital tract: Menorrhagia, pregnancy
• Malabsorption/reduced uptake: Coeliac disease, gastrectomy or bariatric surgery; long-term acid suppression may contribute
• Dietary: Rarely the sole cause in adults (more relevant in paediatrics — excessive cow's milk intake)

Iron deficiency anaemia vs Anaemia of chronic disease — The critical comparison: ^[1]

Causes of anaemia of chronic disease: ^[1]

• Infections
• Cancer
• Autoimmune diseases
• Chronic rejection after solid-organ transplantation
• Chronic kidney disease and inflammation

Proposed mechanisms of anaemia of chronic illness: ^[1]

1. Infection / inflammation → cytokines + LPS → ↑ hepcidin production by the liver
2. Hepcidin ↓ iron absorption in gut mucosa (blocks ferroportin on enterocytes)
3. Hepcidin ↓ iron release from macrophages (blocks ferroportin on macrophages)
4. Net effect: iron is trapped in the reticuloendothelial system → unavailable for erythropoiesis → anaemia

The hepcidin story from first principles:

• Ferroportin is the ONLY known iron exporter on cell surfaces (enterocytes, macrophages, hepatocytes)
• Hepcidin (produced by liver) binds to ferroportin → ferroportin is internalized and degraded
• In inflammation, IL-6 is the key driver of hepcidin transcription (via JAK-STAT3 pathway)
• Result: iron is "locked" inside cells even though total body iron is normal or elevated
• This explains why ferritin is normal/high (iron stores are full) but serum iron is low (iron can't get out)

The lecture diagram shows hepcidin blocking both: ^[1]

• Macrophage iron release (recycling pathway)
• Gut mucosal iron absorption (intake pathway)

• Blunted EPO response: Cytokines (TNF-α, IL-1, IFN-γ) suppress erythropoietin production and reduce erythroid progenitor responsiveness
• Shortened RBC survival: Inflammatory state mildly shortens RBC lifespan
• Direct marrow suppression: Some cytokines inhibit erythroid precursors

Which is the most important source of vitamin B12? → Animal and dairy products ^[1]

Reliable sources include fish, meat, poultry, eggs and dairy products, plus B12-fortified cereals/nutritional yeast and supplements. Most unfortified plant foods are not dependable sources; for example, tempeh contains only a small amount, so the label matters. ^[1][14]

Why animal products? B12 is synthesized only by microorganisms. Animals accumulate it in their tissues. Humans cannot absorb enough B12 from gut bacterial synthesis alone (bacteria produce it in the colon, past the absorption site in the terminal ileum).

The pathway: ^[1]

1. B12 in food → released by gastric acid and pepsin
2. Binds to R-protein (haptocorrin) in saliva/stomach
3. In duodenum, pancreatic proteases cleave R-protein
4. B12 binds to Intrinsic Factor (IF) (secreted by gastric parietal cells)
5. B12-IF complex absorbed at the terminal ileum via cubilin receptor

Pathophysiology of B12 deficiency:

• Deficient/defective IF or release in stomach (pernicious anaemia, gastrectomy)
• Defective absorption of B12-IF complex at terminal ileum (Crohn's disease, ileal resection, bacterial overgrowth)

Lecture-era MCQ answer: "pernicious anaemia." ^[1]

That answer is not universal: the leading cause varies with age, diet, medicines, gastrointestinal disease and population. Current NICE guidance deliberately does not claim autoimmune gastritis is the commonest cause. Use autoimmune gastritis for the underlying disease; "pernicious anaemia" is its late haematological manifestation when severe B12 deficiency produces anaemia. Autoimmune corpus gastritis causes hypochlorhydria and eventual intrinsic-factor loss. ^[9]

Other causes include inadequate intake (especially an unsupplemented vegan diet), metformin, long-term acid suppression, nitrous oxide exposure (functional inactivation), gastric/bariatric surgery, pancreatic insufficiency, coeliac disease, terminal ileal Crohn disease/resection and bacterial overgrowth. Large body stores mean purely dietary deficiency may take years to declare itself, but do not use that delay to exclude deficiency.

Two key intracellular reactions: ^[1]

1. Methylmalonyl CoA → Succinyl CoA (requires adenosylcobalamin in mitochondria)
   • Deficiency → ↑ methylmalonic acid (MMA), a useful functional marker; the neurological injury mechanism is more complex than "MMA causes demyelination"
2. Homocysteine → Methionine (requires methylcobalamin in cytoplasm)
   • This reaction also converts methyl-THF → THF (tetrahydrofolate)
   • THF is needed for DNA synthesis (thymidylate synthesis)
   • Deficiency → ↑ homocysteine + impaired DNA synthesis → megaloblastic change

The "methyl-folate trap": When B12 is deficient, methyl-THF cannot be efficiently converted back to THF for DNA synthesis. Folate alone may correct the blood count while leaving B12-related neurological injury untreated; this can delay recognition. Check/treat B12 promptly rather than claiming folate directly "diverts" B12 or causes the neuropathy.

From the lecture diagram: ^[1]

• Extracellular: B12 circulates bound to haptocorrin (TCIII) — carries most circulating B12 but delivers it mainly to the liver
• Cellular uptake: B12 bound to Transcobalamin II (TCII) binds the TCII receptor on target cells → endocytosis → lysosomal processing releases free B12 for intracellular reactions
• Intracellular B12 then enters two pathways:
  1. Cytoplasm: Homocysteine → Methionine (with MethylTHF → THF → DNA synthesis)
  2. Mitochondria: Methylmalonyl CoA → Succinyl CoA

Clinical features: ^[1]

• Incidental finding of macrocytic anaemia
• Anaemia symptoms (fatigue, SOB)
• Early greying of hair is shown in the deck but is non-specific and should not drive the diagnosis
• Mild jaundice (intramedullary haemolysis — defective erythroblasts die in marrow)
• Glossitis: beefy-red tongue
• Angular stomatitis
• Neuropathy: subacute combined degeneration of the cord (SCDC)

Why jaundice? Megaloblastic erythropoiesis is ineffective: precursors die in the marrow, producing a very high LDH, indirect hyperbilirubinaemia and an inappropriately low corrected reticulocyte response despite the apparently "haemolytic" chemistry. Severe B12 deficiency can therefore mimic a thrombotic microangiopathy, but usually has macro-ovalocytes/hypersegmentation, striking LDH and poor marrow output rather than a brisk reticulocytosis.

Subacute combined degeneration: B12 deficiency can injure the dorsal columns (proprioception/vibration) and lateral corticospinal tracts (UMN pattern), causing paraesthesia, sensory ataxia and later spastic weakness. Neurological disease can occur without anaemia or macrocytosis, so do not let a normal MCV falsely reassure you. ^[7][9]

Key laboratory findings: ^[1]

• Pancytopenia (all lineages affected because DNA synthesis is impaired in all rapidly dividing cells)
• Macrocytic anaemia (MCV often > 110 fL)
• Intramedullary haemolysis: elevated unconjugated bilirubin and LDH
• Blood film: hypersegmented neutrophils and macroovalocytes

Investigations: ^[1]

• Total B12 or active B12 (holotranscobalamin) — either can be the initial test; use the laboratory's assay-specific cut-offs
• Serum methylmalonic acid (MMA) — useful when total/active B12 is indeterminate and symptoms persist; renal impairment can elevate MMA
• Serum folate — when folate deficiency is plausible; routine red-cell folate is usually unnecessary
• Anti-intrinsic-factor antibody — consider if autoimmune gastritis is suspected; a positive result strongly supports it, but a negative result does not exclude it
• Parietal-cell antibody, gastrin or specialist evaluation — selective second-line options when suspicion persists; parietal-cell antibody alone is not diagnostic
• Endoscopy with topographical biopsies — not a reflex blood-test result. NICE emphasizes referral for new/worsening upper-GI symptoms; AGA advises baseline endoscopy for a new pernicious-anaemia diagnosis without a recent examination, to confirm corpus-predominant atrophy and exclude prevalent adenocarcinoma or type-1 gastric neuroendocrine tumour. Follow local gastroenterology practice and individual risk. ^[9][15]
• Schilling test — historical interest only, obsolete in HK
• Bone marrow examination — NOT routinely needed, except when laboratory findings incompatible with PA

The commonly used test for investigation of B12 deficiency: Serum total vitamin B12 level ^[1]

Sources: Green leafy vegetables, fruits, fortified cereals, liver — unlike B12, folate stores last only ~4 months.

Causes of folate deficiency:

• Inadequate dietary intake (alcoholism, anorexia, poor diet)
• Malabsorption (coeliac disease, tropical sprue, IBD, gastric bypass)
• Increased requirements (pregnancy, chronic haemolytic anaemia, exfoliative skin disease, haemodialysis)
• Drug-induced: Methotrexate (DHFR inhibitor), trimethoprim, anticonvulsants (phenytoin, carbamazepine, valproate)

Clinical features: Similar to B12 deficiency (macrocytic anaemia, glossitis, angular cheilitis) BUT:

• Mouth ulcers are more common in folate deficiency
• Neurological features (SCDC) are much less prominent — mainly ascribed to B12 deficiency

• 70M, malaise, low back pain, pallor
• Hb 5.7, MCV 88, WBC 5.2, Plt 92. Blood film: Rouleaux
• Rouleaux reflects increased plasma proteins reducing RBC repulsion; it is a clue, not proof of myeloma.
• Deck sequence: serum globulin, then serum protein electrophoresis (SPEP).
• Current work-up: SPEP plus immunofixation and serum free-light-chain assay (with urine studies when indicated), quantitative immunoglobulins, CBC, renal function and calcium. SPEP alone can miss light-chain disease; confirmation/staging requires marrow assessment and appropriate whole-body imaging.
• Lesson: Rouleaux + bone pain + normocytic anaemia in elderly = think myeloma

• 60F, dizziness, unsteady gait
• Hb 5.7, MCV 128, WBC 2.0, Plt 59 (pancytopenia), Retic 3%, Bili 100, LDH 1890
• Next investigation → Peripheral blood smear (shows hypersegmented neutrophils + macroovalocytes)
• Current next tests: total or active B12, serum folate and anti-IF if autoimmune gastritis is suspected; MMA clarifies an indeterminate B12 result. Routine red-cell folate and a blanket antibody panel are not required.
• The quoted reticulocyte count of 3% is misleading until corrected for the profound anaemia; the production response is inadequate, supporting ineffective erythropoiesis.
• Endoscopy depends on the autoimmune-gastritis diagnosis, symptoms and local risk pathway as described above; bone marrow is reserved for discordant/unclear cases and the Schilling test is obsolete.
• Lesson: Very high MCV + pancytopenia + very high LDH/indirect bilirubin + low effective reticulocyte output = severe megaloblastic anaemia. Establish B12/folate status and cause rather than assuming autoimmune gastritis from the CBC alone.

• 60F, metallic mitral valve (chronic rheumatic valve disease), on warfarin
• Hb 6.7, MCV 99, Plt 259, Bili 60, LDH 690
• Next → Peripheral blood film (fragmented cells support mechanical shear) plus reticulocytes, bilirubin fractions, LDH, haptoglobin, urinalysis and DAT; simultaneously exclude bleeding on warfarin.
• Then → Echocardiography (assess prosthetic function and especially paravalvular regurgitation; use TEE if needed).
• Lesson: This is large-vessel/mechanical fragmentation, not automatically thrombotic microangiopathy. The film supports the mechanism but does not "clinch" the valve lesion by itself.

• 53M, poorly controlled DM + HTN, ankle oedema, pale
• Hb 6.7, MCV 88, normochromic normocytic
• Next → Kidney function (creatinine 890 μmol/L supports advanced kidney disease, with relative EPO deficiency among several mechanisms)
• After EPO replacement × 3 months: Hb only 7.7 but MCV dropped to 68 → now microcytic
• Deck answer for persistent microcytosis → occult blood-loss iron deficiency plus iron-restricted erythropoiesis. Confirm with ferritin/TSAT and evaluate other ESA-hyporesponsiveness causes rather than choosing from MCV alone.
• Lesson: EPO drives erythropoiesis but needs iron as substrate. If iron is insufficient, the marrow cannot respond.

• 78M, OA, on NSAIDs, malaise/SOB/dizziness
• Hb 8.5, MCV 70, WBC 14, Plt 719. Blood film: hypochromic microcytic + pencil cells
• Deck answer "serum iron" is outdated: serum iron varies diurnally and is low in both IDA and inflammation. Order ferritin plus TSAT/TIBC (and interpret CRP/inflammation).
• In an older man with confirmed IDA, investigate the cause urgently. Standard assessment includes history/exam, urinalysis, coeliac screening and usually bidirectional endoscopy (upper endoscopy plus colon evaluation), not upper endoscopy alone; do not let plausible NSAID use hide colorectal or other pathology. ^[10]
• The vignette's upper endoscopy found bleeding gastritis, making NSAID injury plausible, but assess H. pylori, malignancy and other lesions from the actual findings/biopsies.
• Cause → NSAID intake for OA
• Lesson: Microcytic anaemia in elderly = IDA until proven otherwise → always look for GI source. Reactive thrombocytosis is common in IDA.

• 19M, immigrant from China, short stature, worsening malaise
• Hb 7.5, MCV 103, WBC 2.0, Plt 109. Blood film: macrocytic anaemia + dysplastic neutrophils
• Image read: short stature, patchy/café-au-lait pigmentation and bilateral hypoplastic/abnormal thumbs point to an inherited DNA-repair/bone-marrow-failure syndrome.
• Family history: similarly affected siblings/consanguinity support the usual autosomal-recessive inheritance, but a negative history does not exclude Fanconi anaemia; rarer inheritance patterns and de novo presentations exist.
• Diagnostic test: chromosome-breakage testing of blood lymphocytes after diepoxybutane (DEB) or mitomycin-C exposure, followed by germline molecular confirmation. If blood testing is negative/equivocal but suspicion remains, test skin fibroblasts because somatic mosaicism can mask the blood result. ^[13]
• Complications: progressive marrow failure, MDS/AML and marked solid-tumour risk (especially head/neck and anogenital squamous cancers). "Leukaemia transformation" is not the only major long-term danger.
• Lesson: Young patient + short stature + pancytopenia + café-au-lait spots + radial/thumb anomalies = think inherited bone marrow failure syndrome → Fanconi anaemia

1. "Which physical sign is NOT associated with IDA?" → Palmar erythema ^[3]
2. "32F with pancytopenia and macrocytosis, pale, no HSM → most likely diagnosis?" → Distinguish between aplastic anaemia vs pernicious anaemia. Key: in PA you get macrocytosis + elevated LDH/bilirubin; in aplastic, the marrow is empty but LDH/bili are normal. ^[3][5]
3. "What is the most useful test to differentiate IDA from ACD?" → Lecture answer: serum ferritin; real cases require ferritin + TSAT and inflammatory context ^[1][10]
4. "Elderly with macrocytic anaemia, glossitis, thyroid disease history, pancytopenia, very high LDH → diagnosis?" → Pernicious anaemia ^[5]
5. "Young woman with low MCV, mild anaemia, low platelets but otherwise well → diagnosis?" → Thalassaemia intermedia with hypersplenism ^[3]