Vitamin B12 Deficiency Anaemia

Overview

Vitamin B₁₂ (cobalamin) deficiency is a common cause of megaloblastic anemia, a variety of neuropsychiatric symptoms, and elevated serum homocysteine levels, especially in older persons. The recognition and treatment of vitamin B₁₂ deficiency is critical since it is a reversible cause of bone marrow failure and demyelinating nervous system disease.

Definition

Anaemia (Anemia): The World Health Organization defines anaemia as a haemoglobin (Hb) concentration below 13 g/dl (130 g/L) in men over 15 years of age, below 12 g/dl (120g/L) in non-pregnant women over 15 years of age, and below 11 g/dl (110g/L) in pregnant women
Iron deficiency anaemia: Most common type of anemia, and it occurs when your body doesn’t have enough of the mineral iron
Microcytic anemia Defined as the presence of small, often hypochromic, red blood cells in a peripheral blood smear and is usually characterized by a low mean cell volume (MCV) (<83 micron3). Iron deficiency is the most common cause of microcytic anemia.
Normocytic anaemia: defined by a normal mean corpuscular volume (MCV), but the hemoglobin and hematocrit are decreased. Usually a result of hemolytic anaemia or anaemia of chronic disease
Mactocytic anaemia (Macrocytosis): defined as a mean corpuscular volume greater than 100 fL, is frequently encountered when a complete blood count is performed. The most common etiologies are alcoholism, vitamin B₁₂ and folate deficiencies, and medications.

Physiology of Vitamin B12 Digestion and Abosorption

Vitamin B12 is found in meat, fish, and dairy products. NOT in plants. The liver can store Vitamin B12 and stores are sufficient for up to 5 years. The daily requirement of vitamin B₁₂ is about 2.4 μg.

Vitamin B12 is found almost exclusively in animal-based foods and is therefore a nutrient of potential concern for those following a vegetarian or vegan diet. Vegans, and anyone who significantly limits intake of animal-based foods, require vitamin B12-fortified foods or supplements.

Vitamin B₁₂ (cobalamin) is a water-soluble vitamin that is crucial to normal neurologic function, red blood cell production, and DNA synthesis.

Aetiology & Risk Factors

Aetiology

Pernicious anemia (autoimmune-mediated chronic atrophic gastritis) – most common cause of severe vitmain b12 deficiency
Postsurgical malabsorption
Dietary deficiencies
Vitamin B₁₂malabsorption from food

Risk Factors

Decreased ileal absorption

Crohn’s disease
Ileal resection
Tapeworm infestation

Decreased intrinsic factor

Atrophic gastritis
Pernicious anaemia
Postgastrectomy syndrome

Genetic

Transcobalamin II deficiency

Inadequate intake

Alcohol abuse
Older persons
Vegetarians

Prolonged medication use

Metformin
Proton pump inhibitors
Histamine h2 blockers

Clinical Manifestations

Clinical manifestations of megaloblastic anemia include pallor, tachycardia, weakness, fatigue, and palpitations. The specific mechanism by which vitamin B₁₂deficiency affects the neurologic system is unknown.

There are extensive hepatic stores of vitamin B_12. There may be a five- to 10-year delay between the onset of deficiency and the appearance of clinical symptoms.

Fatigue
Short of breath
Headache
Pallor, hyperpigmentation
Muscle Weakness
Dizziness and Confusion
Paraesthesia (numbness)
Ataxia (loss of normal control of body movements)
Atropic Glosstis (smooth erythematous surface of tongue)

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Peripheral neuropathy is the most common symptom of vitamin B12 deficiency. Folate deficiency alone typically has no neurological symptoms.

Differential Diagnosis

DIFFERENTIAL DIAGNOSIS OF MACROCYTIC ANAEMIA (MACROCYTOSIS)
Macrocytic Anaemia	Clinical Features	Investigations
Vitamin B12 deficiency	paresthesias related to peripheral neuropathy, poor or strict vegan diet, lack of socioeconomic resources, bowel-related symptoms (including diarrhea), or a history of bowel surgery for weight loss. Findings on physical examination may include neurologic signs such as ataxia, decreased proprioception, and vibratory sensation. Patients may also have poor dentition or nonspecific oral stomatitis or glossitis.	Serum Vitamin B12.
Alcohol excess	Physical findings consistent with alcoholism include gynecomastia, caput medusae, and jaundice.	The mean corpuscular volume is generally less than 110 fL with chronic alcohol use. Abstinence from alcohol rapidly corrects the elevated mean corpuscular volume
Reticulocytosis	Family History of haemotological syndromes (sickle cell disease, hereditary spherocytosis, G6P dehydrogenase deficiency). Examination may reveal hepatosplenomegaly in hemolysis or other physical manifestations of blood loss (e.g., conjunctiva, mucosal pallor	Peripheral smear will reveal evidence of hemolyzed RBCs (e.g., bite cells, helmet cells)
Myeloproliferative disorders	Splenomegaly, hepatomegaly, fatigue	Bone marrow biopsy is required to establish this diagnosis
Hypothyroidism	Mental sluggishness, obese, fatigue, sleepy	Thyroid function test
Folate deficiency		Serum folate levels are not useful. RBC folate levels is more accurate.

In differentiating the cause of megaloblastic anemia, a methylmalonic acid level that is within normal range also points toward a diagnosis of folate deficiency, especially if the serum vitamin B₁₂ level is within the normal range. Note that homocysteine levels will be elevated with vitamin B₁₂ and folate deficiencies.

Investigations

Both the clinical recognition of vitamin B₁₂ deficiency and confirmation of the diagnosis by means of testing can be difficult.

FBC
Blood smear
- Macrocytic anaemia
- Hypersegmented neutrophils
Serum vitamin B₁₂ level
Serum folate
Methylmalonic acid – more sensitive and specific for the diagnosis.
Homocysteine
Anti–intrinsic factor antibodies (pernicious anaemia)

Classic hematologic expression of vitamin B₁₂ deficiency is a megaloblastic macrocytic anemia characterized by an elevated mean corpuscular volume and mean corpuscular hemoglobin, and a peripheral smear containing macroovalocytes and hypersegmented neutrophils.

Serum vitamin B12 levels can be normal even in vitamin B12 deficiency. This is because during periods of stress, the body will produce more transcobalamin (carrier protein for VB12). Measuring methylmalonic acid is thus more sensitive.

Treatment

High-dose oral Vitamin B12 supplements
Parenteral cyanocobalamin or hydroxocobalamin
Multivitamins – for vegans

Complications & Prognosis

Exclusively breastfed children of mothers with vitamin B₁₂ deficiency are at increased risk of failure to thrive, hypotonia, ataxia, developmental delays, anemia, and general weakness.

Complications

Neurolgical deficits
Haemotological deficits
Gastric cancer (pernicious anaemia)

Prognosis

Vitamin B12 deficiency can cause devastating neurological disease and severe haematological disorders. Early diagnosis and prompt treatment may reverse neurological disease. Unfortunately, many cases are irreversible and clinical disease may not respond to adequate therapy.

References

BestPractice
Langan, RC., Zawistoski, KJ. (2011). Update on Vitamine B12 Deficiency. American Family Physician. 83 (12). 1425-1430.
Stabler, SP. (2013). Vitamin B12 Deficiency. New England Journal Of Medicine. 368. 149-160.