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Anaemia

Vitamin B12 and folate deficiency

Prevalence

Vitamin B12 (cobalamin) and folate deficiency are both implicated in nearly 20% of anaemias reported in older adults (aged >65 years).1 Folate deficiency is particularly frequent in the elderly, due to dietary habits.

Causes

Vitamin B12 deficiency has various causes, each impacting at a particular point in the overall metabolism of the compound:2

Stage of metabolismCauses of vitamin B12 deficiency
IngestionStrict vegetarianism
DigestionGastrectomy, pernicious anaemia, and food-cobalamin malabsorption
AbsorptionIleal resection, malabsorption, pernicious anaemia, and food-cobalamin malabsorption
TransportationCongenital deficiency in transcobalamin II
Intracellular metabolismCongenital deficiency in various intracellular enzymes

The most common causes of Vitamin B12 deficiency in elderly patients are malabsorption and pernicious anaemia (idiopathic atrophy of gastric mucosa in association with antibodies to parietal cells and/or intrinsic factor). Dietary deficiency of Vitamin B12 is rare (< 5%) among healthy adults in industrialised countries, even among elderly people.3

Unlike vitamin B12 deficiency, folate deficiency is usually the result of inadequate dietary intake. The body stores very little folate (only enough to last around four months) so reserves can be exhausted relatively quickly.4 Other causes of folate deficiency include intestinal malabsorption, excessive alcohol intake, presence of psoriasis or other medical conditions with increased cell proliferation, and the use of folate antagonist drugs (e.g. anti-epileptics, oestroprogestinics, methotrexate).5

Clinical symptoms

Vitamin B12 deficiency may be asymptomatic, or may manifest with myriad neurologic and/or haematologic features.6 The main clinical manifestations of Vitamin B12 deficiency include:3

Haematological
FrequentMacrocytic anaemia, hypersegmentation of the neutrophils, aregenerative macrocytary anaemia, LDH and bilirubin elevation, medullary megaloblastosis
RareIsolated thrombocytopenia and neutropenia, pancytopenia
Very rareHaemolytic anaemia, thrombotic microangiopathy
Neuropsychiatric
FrequentPolyneurites (especially sensitive ones), ataxia, Babinski's phenomenon
ClassicCombined sclerosis of the spinal cord
RareCerebellar syndromes affecting the cranial nerves including optic neuritis, optic atrophy, urinary and/or faecal incontinence
Digestive
ClassicHunter's glossitis, jaundice, LDH and bilirubin elevation
RareResistant and recurring mucocutaneous ulcers

As with vitamin B12 deficiency, folate deficiency usually causes macrocytic anaemia. Note however, that a significant proportion (25%) of elderly patients with folate deficiency have normocytic anaemia, due to concomitant iron deficiency or other pathologies.4

Diagnosis

A serum B12 measurement is a reasonable initial screening test, with levels less than 100 pg/ml suggesting deficiency. However, levels of 100–400 pg/ml do not reflect true tissue levels, and in this case additional tests (homocysteine and methylmalonic acid) should be considered.6

Note that various conditions can cause misleading vitamin B12 levels as a consequence of false positive and false negative results.6

False positives (false low levels) may occur with:
  • Folate deficiency
  • Use of oestroprogestinics
  • Multiple myeloma
  • Excessive vitamin C intake
False negatives (normal levels of B12) may occur with:
  • Active liver disease
  • Lymphoma
  • Alcoholism
  • Intestinal bacterial overgrowth
  • Myeloproliferative disorders

Folate deficiency is usually defined as a serum folate < 5 nmol/l. Because individuals with reduced folate status have elevated levels of homocysteine, a finding of low or borderline levels of folate with elevated levels of homocysteine can be defined as metabolically significant folate deficiency.5

Treatment and follow-up

The classic treatment for vitamin B12 deficiency, particularly when the cause is not dietary deficiency (e.g. pernicious anaemia, malabsorption), is intramuscular injection of the vitamin. However, dose and administration schedule vary considerably between countries. In cases of dietary deficiency, the oral route has been proven effective.2

If vitamin B12 deficiency is associated with severe anaemia, correction of the deficiency state should lead to a marked reticulocytosis in about one to two days. In mild vitamin B12 deficiency, repeated measurements of serum vitamin B12, homocysteine, and methylmalonic acid levels, two to three months after initiating treatment, is recommended.

Folate deficiency is normally treated with oral folic acid.4 In cases of severe malabsorption, parenteral administrations may be considered. Dietary advice (e.g. increased consumption of salad and raw vegetables) may also be appropriate to help the elderly patient increase dietary folate intake. Correction of folate levels usually requires about 4 months’ treatment, although longer treatment periods may be required in patients where the deficiency has a persistent underlying cause (e.g. alcoholism).

Follow-up is important to determine the patient’s response to therapy.

References

  1. Patel KV. Epidemiology of anaemia in older adults. Semin Hematol. 2008;45(4):210-7.
  2. Andrès E, Vogel T, Federici L, et al. Cobalamin deficiency in elderly patients: a personal view. Curr Gerontol Geriatr Res. 2008:848267.
  3. Andrès E, Loukili NH, Noel E, et al. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ. 2004;171(3):251-9.
  4. Smith DL. Anaemia in the Elderly. Am Fam Physician. 2000;62(7):1565-72.
  5. Clarke R, Evans JG, Schneede J, et al. Vitamin B12 and folate deficiency in later life. Age Ageing. 2004;33:34-41.
  6. Dharmarajan TS, Adiga GU, Norkus EP. Vitamin B12 deficiency. Recognizing subtle symptoms in older adults. Geriatrics. 2003;58(3):30-8.
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