Clinical history—review potential sources of blood loss, especially GIT loss.

Menstrual loss— quantitation may be difficult; ask about number of tampons used per day, how often these require changing, and duration.

Other sources of blood loss e.g. haematuria and haemoptysis (these are not common causes of iron deficiency). Ask patient if he/she has been a blood donor—regular blood donation over many years may cause chronic iron store depletion.

Drug therapy e.g. NSAIDs and corticosteroids may cause GI irritation and blood loss.

Past medical history e.g. previous gastric surgery (—^malabsorption). Ask about previous episodes of anaemia and treatments with iron.

In patients with iron deficiency assume underlying cause is blood loss until proved otherwise. In developed countries pure dietary iron lack causing iron deficiency is almost unknown.


• General examination including assessment of mucous membranes (e.g. hereditary haemorrhagic telangiectasia).

• Seek possible sources of blood loss.

• Abdominal examination, rectal examination and sigmoidoscopy mandatory.

• Gynaecological examination also required.

Laboratory tests

• 5 MCV (<76FLz) and 5 MCHC (note: 5 MCV in thalassaemia and ACD).

• Red cell distribution width (RDW): 4 in iron deficiency states with a greater frequency than in ACD or thalassaemia trait.

• Serum ferritin (measurement of iron/TIBC generally unhelpful). Ferritin assay preferred—a low serum ferritin identifies the presence of iron deficiency but as an acute phase protein it can be 4, masking iron deficiency. 5 iron and 4 TIBC indicates iron deficiency.

• The soluble transferrin assay (sTfR) is useful in cases where 4 ESR. sTfR is 4 in iron deficiency but in anaemia in presence of 4 ESR (e.g. rheumatoid, other inflammatory states). This assay is not universally available at present.

• % hypochromic RBCs—some modern analysers provide this parameter. 4% hypo RBCs are seen in iron deficiency but also thalassaemia, CRF on Epo where insufficient iron given.

• Zinc protoporphyrin (ZPP)—in the absence of iron, zinc is incorporated into protoporphyrin and can be measured.

• Examination of BM aspirate (iron stain) is occasionally useful.

• Theoretically FOB testing may be of value in iron deficiency but results can be misleading. False +ve results seen in high dietary meat intake.

Blood film in iron deficiency anaemia: note pale red cells with pencil cell (top left).

Treatment of iron deficiency

Simplest, safest and cheapest treatment is oral ferrous salts, e.g. FeSO4 (Fe gluconate and fumarate equally acceptable). Provide an oral dose of elemental iron of 150-200mg/d. Side effects in 10-20% patients (e.g. abdominal distension, constipation and/or diarrhoea)—try 5 the daily dose to bd or od. Liquid iron occasionally necessary, e.g. children or adults with swallowing difficulties. Increasing dietary iron intake has no routine place in the management of iron deficiency except where intake is grossly deficient.

Response to replacement

A rise of Hb of 2.0g/dL over 3 weeks is expected. MCV will 4 concomitantly with Hb. Reticulocytes may 4 in response to iron therapy but is not a reliable indicator of response.

Duration of treatment

Generally ~6 months. After Hb and MCV are normal continue iron for at least 3 months to replenish iron stores.

Failure of response

• Is the diagnosis of iron deficiency correct?

- Consider anaemia of chronic disorders or thalassaemia trait.

• Is there an additional complicating illness?

- Chronic infection, collagen disorder or neoplasm.

• Is the patient complying with prescribed medication?

• Is the preparation of iron adequate in dosage and/or formulation?

• Is the patient continuing to bleed excessively?

• Is there malabsorption?

• Are there other haematinic deficiencies (e.g. B12 or folate) present?

• Reassess patient: ?evidence of continued blood loss or malabsorption.

Parenteral iron

Occasionally of value in genuine iron intolerance, if compliance is a problem, or if need to replace stores rapidly e.g. in pregnancy or prior to major surgery. Note: Hb will rise no faster than with oral iron.

Intravenous iron Iron may be administered IV as iron hydroxide sucrose complex.

Intramuscular iron e.g. iron sorbitol citrate. Usually ~10-20 IM injections over several week period (note: injections painful and lead to long-term skin discoloration at the injection site). Best avoided.

Andrews, N.C. (1999) Disorders of iron metabolism. N Engl J Med, 341, 1986-1995; Kuhn, L.C. & Hentze, M.W. (1992) Coordination of cellular iron metabolism by post-transcriptional gene regulation. J Inorg Biochem, 47, 183-195; Tapiero, H., Gate, L & Tew, K.D. (2001) Iron: deficiencies and requirements. Biomed Pharmacother, 55, 324-332.

B12 deficiency presents with macrocytic, megaloblastic anaemia ranging from mild to severe (Hb <6.0g/dL). Symptoms are those of chronic anaemia, i.e. fatigue, dyspnoea on effort, etc. Neurological symptoms may also be present—classically peripheral paraesthesiae and disturbances of 60 position and vibration sense. Occasionally neurological symptoms occur with no/minimal haematological upset. If uncorrected, the patient may develop subacute combined degeneration of the spinal cord—►permanently ataxic.


B12 (along with folic acid) is required for DNA synthesis; B12 is also required for neurological functioning. B12 is absorbed in terminal ileum after binding to intrinsic factor produced by gastric parietal cells. Body stores of B12 are 2-3mg (sufficient for 3 years). B12 is found in meats, fish, eggs and dairy produce. Strictly vegetarian (vegan) diets are low in B12 although not all vegans develop clinical evidence of deficiency.

Presenting haematological abnormalities

• Macrocytic anaemia (MCV usually >110fL). In extreme cases RBC anisopoikilocytosis can result in MCV values lying just within normal range.

• RBC changes include oval macrocytosis, poikilocytosis, basophilic stippling, Howell-Jolly bodies, circulating megaloblasts.

• Hypersegmented neutrophils.

• Leucopenia and thrombocytopenia common.

• Bone marrow shows megaloblastic change; marked erythroid hyperplasia with predominance of early erythroid precursors, open atypical nuclear chromatin patterns, mitotic figures and 'giant' metamyelocytes.

• Serum/red cell folate usually or 4.

• LDH levels markedly 4 reflecting ineffective erythropoiesis.

• Autoantibody screen in pernicious anaemia: 80-90% show circulating gastric parietal cell antibodies, 55% have circulating intrinsic factor antibodies. Note: parietal cell antibodies are not diagnostic since found in normals; IFA is only found in 50% of patients with PA but is diagnostic.

Causes of B12 deficiency

Pernicious anaemia Commonest, due to autoimmune gastric atrophy resulting in loss of intrinsic factor production required for absorption of B12. Incidence increases >40 years and often associated with other autoimmune problems, e.g. hypothyroidism.

Following total gastrectomy May develop after major partial gastrectomy.

Ileal disease Resection of ileum, Crohn's disease.

Blind loop syndromes

E.g. diverticulae or localised inflammatory bowel changes allowing bacterial overgrowth which then competes for 61 available B12.

Fish tapeworm Malabsorptive disorders Dietary deficiency

Tropical sprue, coeliac disease.

Diphyllobothrium latum.

Management of B12 deficiency

1. Identify and correct cause if possible.

2. Above investigations are undertaken and a test of B12 absorption is carried out (e.g. Schilling test). Urinary excretion of a test dose of B12 labelled with trace amounts of radioactive cobalt is compared with excretion of B12 bound to intrinsic factor*; the test is done in two parts. B12 malabsorption corrected by intrinsic factor is diagnostic of pernicious anaemia (in absence of previous gastric surgery).

3. Management—hydroxocobalamin 1mg IM and folic acid PO should be given immediately.

4. Supportive measures—bed rest, O2 and diuretics may be needed while awaiting response. Transfusion is best avoided but 2 units of concentrated RBCs may be used for patients severely compromised by anaemia (risk of precipitating cardiac failure); hypokalaemia is occasionally observed during the immediate response to B12 and serum [K+] should be monitored.

5. Response apparent in 3-5d with reticulocyte response of >10%; normoblastic conversion of marrow erythropoiesis in 12-24h. Patients frequently describe a subjective improvement within 24h.

6. B12 replacement therapy—initially hydroxocobalamin 5 x 1mg IM should be given during the first 2 weeks, thereafter maintenance injections are needed 3-monthly.

7. If dietary deficiency seems likely and B12 deficiency mild, worth trying oral B12 (cyanocobalamin 50-150|mg or more, daily between meals)

8. Long term follow-up depends on the primary cause. Pernicious anaemia patients require lifelong treatment and should be checked annually with a full blood count and thyroid function; the incidence of gastric cancer is twice as high in these patients compared to the normal population.

9. Broad spectrum antibiotics should be given to suppress bacterial overgrowth in blind loop syndrome ± local surgery if appropriate. Long term IM B12 may be the pragmatic solution if blind loop cannot be corrected.

*Worldwide shortage of intrinsic factor at present, due to worries about human prion disease.

This means that only part I Schilling test available in most centres.

Guidelines on the investigation and diagnosis of cobalamin and folate deficiencies. A publication of the British Committee for Standards in Haematology. BCSH General Haematology Test Force

(1994). Clin Lab Haematol, 16, 101-115; Toh, B.H., van Driel, I.R. & Gleeson, P.A. (1997)

Pernicious anemia. N Engl J Med, 337, 1441-1448.

Folate deficiency represents the other main deficiency cause of megaloblastic anaemia; haematological features indistinguishable from those of B12 deficiency. Distinction is on basis of demonstration of reduced red cell and serum folate.

►► Megaloblastic anaemia patients should never receive empirical treatment with folic acid alone. If they lack B12, folic acid is potentially capable of precipitating subacute combined degeneration of the cord.


Adult body folate stores comprise 10—15mg; normal daily requirements are 0.1-0.2mg, i.e. sufficient for 3-4 months in absence of exogenous folate intake. Folate absorption from dietary sources is rapid; proximal jejunum is main site of absorption. Main dietary sources of folate are liver, green vegetables, nuts and yeast. Western diets contain ~0.5-0.7mg folate/d but availability may be lessened as folate is readily destroyed by cooking, especially in large volumes of water. Folate coenzymes are an essential part of DNA synthesis, hence the occurrence of megaloblastic change in deficiency.


Haematological findings are identical to those seen in B12 deficiency— macrocytic, megaloblastic anaemia. Other findings also similar to B12 except parietal cell and intrinsic factor autoantibodies usually -ve. Reduced folate levels—serum folate levels reflect recent intake, red cell folate levels give a more reliable indication of folate status.

Causes of folate deficiency

5 intake Poor nutrition, e.g. poverty, old age, 'skid row' alcoholics.

4 requirements/losses Pregnancy, 4 cell turnover, e.g. haemol ysis, exfoliative dermatitis, renal dialysis.

Malabsorption Coeliac disease, tropical sprue, Crohn's and other malabsorptive states.

Drugs Phenytoin, barbiturates, valproate, oral contraceptives, nitrofurantoin may induce folate malabsorption.

Antifolate drugs Methotrexate, trimethoprim, pentami dine antagonise folate cf. induce deficiency.

Alcohol Poor nutrition plus a direct depressant effect on folate levels which can precipitate clinical folate deficiency.


1. Treatment and support of severe anaemia as for B12 deficiency.

2. Folic acid 5mg/d PO (never on its own—see above), unless patient known to have normal B12 level.

3. Treatment of underlying cause e.g. in coeliac disease folate levels and 63 absorption normalize once patient established on gluten-free diet. Long term supplementation advised in chronic haemolysis e.g. HbSS or HS.

4. Prophylactic folate supplements recommended in pregnancy and other states of increased demand e.g. prematurity.

Blood film: normal neutrophil: usually has <5 lobes. This one has 3 lobes.

Hypersegmented neutrophils with 7-8 lobes: found in B or folate deficiency. Note: blood films and marrow appearances are identical in B12 and folate deficiencies.

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