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EBMG

Megaloblastic Anaemia

Essentials

  • Suspect megaloblastic anaemia if the patient presents with macrocytosis, i.e. increased erythrocyte mean cell volume (MCV).
  • Establish the aetiology of the anaemia (usually deficiency of vitamin B12 or folates).
  • Establish the reason for vitamin deficiency.
  • Start specific treatment and monitor treatment response.

Symptoms

  • In mild cases, the signs and symptoms are mainly related to the anaemia, but other cytopenias are also possible (thrombocytopenia and leucocytopenia).
  • In more advanced cases the patient may also present with
    • weight loss
    • glossitis
    • jaundice.
  • Neurological symptoms associated with vitamin B12 deficiency include: paraesthesias caused by myelopathy, limb weakness, ataxia, and central nervous system symptoms, such as cognitive disturbances, depression and delusions. These may become evident before the haematological symptoms and may be irreversible.

Signs

  • Megaloblastic anaemia is usually associated with an increased MCV value, i.e. macrocytosis.
    • Other causes of macrocytosis include an increased number of reticulocytes (acute bleeding or haemolysis), chronic liver disease, excessive alcohol consumption, hypothyroidism and, rarely, aplastic anaemia or malignant blood diseases (e.g. myelodysplastic syndrome).
  • Megaloblastic anaemia is usually caused by a deficiency of vitamin B12 or folates. Aetiological investigations include
    • Transcobalamin II-bound vitamin B12
    • Serum folate concentration (according to current understanding correlates equally well to folate deficiency as the determination of erythrocyte folate, and its analytical variation is smaller than that of erythrocyte folate determination).
  • Megaloblastic anaemia is associated with the premature breaking down of red blood cell precursors in the bone marrow, which leads to an increase in the concentration of plasma lactate dehydrogenase and bilirubin and to a decrease in the haptoglobin concentration.

Causes of megaloblastic anaemia

Vitamin B12 deficiency

  • Vitamin B12 deficiency is usually due to malabsorption. Underlying causes may include:
    • classic pernicious anaemia (an autoimmune disease) or atrophic gastritis, which may be associated with Helicobacter pylori infection. These conditions are caused by a lack of intrinsic factor (IF), a substance needed to absorb vitamin B12. In the non-acid stomach, vitamin B12 is not released from dietary proteins, thus preventing the absorption of protein-bound vitamin B12 from the gastrointestinal tract.
    • disease affecting the terminal ileum; inhibited binding of the IF/vitamin B12 complex to a specific receptor.
    • bariatric surgery Bariatric Surgery (Obesity Surgery) if the patient has not used vitamin B12 substitution.
  • Rare causes include partial or total gastrectomy, bowel resection involving the terminal ileum and tapeworm infestation (competes with the host for vitamin B12), Gräsbeck-Imerslund syndrome.
  • A strict vegan diet may contribute towards a low vitamin B12 concentration, but it very seldom causes megaloblastic anaemia.

Folate deficiency

  • Dietary deficiency (often in alcoholics; so-called goat's milk anaemia in children)
  • Increased requirements (pregnancy, prematurity, haemolysis, cancer)
  • Malabsorption (coeliac disease, Crohn's disease, intestinal resections)
  • Parenteral nutrition without folate substitution
  • Increased loss (some skin and liver diseases, dialysis)

Drugs and chemicals that may cause B12 or folate deficiency

  • Folic acid antagonists: methotrexate, trimethoprim, triamterene at high doses
  • Purine analogues (antineoplastic and antiviral drugs and immunosuppressives): aciclovir, azathioprine, mercaptopurine, tioguanine
  • Pyrimidine analogues (antineoplastic and antiretroviral drugs): azacytidine, fluorouracil, cytarabine, stavudine, zidovudine
  • Ribonucleotide reductase inhibitors (antineoplastic drugs): hydroxyurea
  • Antiepileptics: phenytoin, phenobarbital, primidone
  • Other drugs that interfere with folate metabolism: oral contraceptives, cycloserine
  • Drugs that interfere with vitamin B12 metabolism: para-aminosalicylic acid, metformin, colchicine, neomycin
  • Others: isoniazid, mefenamic acid, nitrofurantoin, pentamidine, pyrimethamine, potassium chloride
  • Drugs that inhibit gastric acid excretion
  • Alcohol, chronic exposure to nitrous oxide (laughing gas)

Diagnostic assessment

  • Can usually be carried out in primary care.
  1. Relevant history focusing on dietary habits (use of meat and dairy products as well as green vegetables) and the gastrointestinal tract (gastritis, Helicobacter pylori status, resections, inflammatory bowel diseases, coeliac disease) is essential.
  2. Determine
    • serum concentration of transcobalamin II-bound vitamin B12
      • Biologically active form
    • fasting serum folate concentration.
  3. If the patient has vitamin deficiency, the underlying cause should be established.
  4. Bone marrow examination is only indicated if you suspect some other cause than vitamin B12 deficiency or if the blood picture abnormalities are not corrected when drugs that might possibly cause macrocytosis have been discontinued.

Additional investigations

  • Vitamin B12 deficiency alone
    • The need for gastroscopy with biopsies should be considered (atrophic gastritis, Helicobacter pylori infection?).
    • If the pathogenesis of vitamin B12 deficiency remains unclear, the patient should be referred to specialized care for further investigations to detect possible malabsorption disorders and to refine the evaluation of the patient's vitamin B12 status.
  • Folate deficiency alone
    • Serum transcobalamin II-bound vitamin B12 concentration normal, fasting serum folate low
    • If indicated, the possibility of malabsorption must be investigated.
  • Normal transcobalamin II-bound vitamin B12 and fasting serum folate concentration
    • It should be established whether the patient is using any medication that is known to cause megaloblastic anaemia. If possible, such medication is discontinued or substituted. Haemoglobin and erythrocyte MCV values are checked after 1-2 months.
  • Combined deficiency of vitamin B12 and folate
    • The aetiology of each condition should be investigated separately (see above).

Treatment Oral Vitamin B12 Versus Intramuscular Vitamin B12 for Vitamin B12 Deficiency

  • Patients with megaloblastic anaemia have usually adapted well to low haemoglobin values.
  • Any samples for vitamin determinations are taken before substitution is started.
  • Vitamin B12 substitution:
    • hydroxycobalamin 1 mg intramuscularly initially every few days for a period of 2 weeks and thereafter 1 mg every 3-4 months or
    • cyanocobalamin orally; initially 2-4 mg daily until an adequate response is reached and thereafter 1 mg daily as maintenance therapy.
    • In neuropathy the initial treatment is more intensive, i.e 1 mg of hydroxycobalamin intramuscularly every other week for up to 6 months.
    • Daily oral folic acid substitution exceeding 1 mg/day should not be started as a treatment for macrocytic anaemia in a patient, even if his/her folate concentration would be low, before an underlying vitamin B12 deficiency has been ruled out. High 5-15 mg daily doses of folate may correct anaemia but mask an underlying vitamin B12 deficiency that potentially causes neurological damage.
    • The efficacy of treatment should be ascertained. If needed, a reticulocyte count can be carried out 5-7 days after initiation of therapy. A good response predicts a favourable outcome. MCV and haemoglobin concentration should be checked after about 1 and 4 months. Thereafter, basic blood count with platelets may be monitored every now and then in order to assure the permanence of remission (especially if there are grounds to suspect patient compliance, but there is no need to monitor the vitamin B12 concentration in patients receiving treatment). During follow-up it should be borne in mind that pernicious anaemia is associated with a slightly increased risk of gastric cancer.
    • If the treatment is not effective, the reason may be simultaneous iron deficiency (MCV decreases but the anaemia persists). The patient's ferritin and transferrin receptor concentrations are determined, and iron therapy started if required..
    • If the treatment continues to be ineffective, the patient should be referred to a specialist in internal medicine or to a haematologist.
  • Folate deficiency is most frequently caused by a deficient diet, and dietary education should be given. Oral substitution is usually sufficient (1 mg/day). Even malabsorption may be managed with oral doses of 5-10 mg/day.
  • Helicobacter eradication therapy should also be considered when necessary.