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

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.