Cobalamin Deficiency

How to Cite This Chapter: Crowther M, Podolak-Dawidziak M. Cobalamin Deficiency. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. Accessed May 22, 2024.
Last Updated: September 2, 2021
Last Reviewed: September 2, 2021
Chapter Information

Also see Anemia: General Considerations.

Definition, Etiology, Pathogenesis Top

Cobalamin (vitamin B12) deficiency leads to an impaired production of erythroblasts, premature destruction of erythroblasts in bone marrow (ineffective erythropoiesis), as well as to a reduced red blood cell (RBC) life-span, consequently causing megaloblastic anemia. The minimum daily intake of cobalamin is 2 to 5 microg. Its main sources are meat and milk products. The body stores of cobalamin cover a 4-year requirement. Cobalamin deficiency manifests in tissues characterized by rapid cell turnover (eg, the gastrointestinal [GI] mucosa) as well as in changes affecting the nervous system (demyelination and peripheral neuropathy).


1) Inadequate cobalamin dietary intake: Vegetarian or vegan diet, alcohol dependency.

2) Cobalamin malabsorption: Pernicious anemia (autoimmune gastritis); congenital intrinsic factor deficiency or intrinsic factor abnormalities; gastrectomy, bariatric surgery, Helicobacter pylori infection, or ileal resection; Crohn disease; bacterial overgrowth syndrome; chronic pancreatitis; Zollinger-Ellison syndrome; congenital selective cobalamin malabsorption; drugs (metformin, inhibitors of gastric acid secretion, nitric oxide used in anesthesia); fish tapeworm and other GI infestations.

3) Transcobalamin II deficiency.

Clinical Features and Natural History Top

1. General symptoms: General symptoms of anemia are observed in advanced disease (see Anemia: General Considerations).

2. GI manifestations are observed in ~50% of patients and involve loss of taste; an enlarged, smoothened, and dark-red tongue; tingling of the tongue; nausea, constipation or diarrhea, weight loss.

3. Nervous system manifestations: Paresthesias affecting the upper and lower extremities (usually the presenting symptom is a tingling sensation in the fingertips), numbness, gait abnormalities, miction abnormalities (these may progress to urinary tract obstruction), autonomic symptoms (orthostatic hypotension, urinary incontinence, sexual dysfunction). The first symptom of so-called “subacute combined degeneration” (demyelination of the dorsal and lateral columns of the spinal cord) is usually loss of position sense in the second toe combined with loss of vibration sense. Patients with severe chronic cobalamin deficiency have abnormal tendon and extrapyramidal reflexes (hyperreflexia or hyporeflexia), decreased muscle tone, visual abnormalities (optic atrophy), or hearing impairment. Psychiatric symptoms include cognitive dysfunction, depression, mania, mood instability, and delusions; in elderly patients, dementia may be the leading feature. Severe untreated cobalamin deficiency leads to irreversible neurologic deficits. The severity of anemia is not always correlated with the degree of neurologic dysfunction.

4. Cutaneous manifestations: Mild jaundice (lemon-yellow or wax-yellow skin), premature graying of hair, in some patients acquired vitiligo, less commonly petechiae.


Diagnostic Tests

1. Complete blood count (CBC): Often profound macrocytosis (this precedes the development of anemia), normochromic RBCs, oval macrocytes, sometimes normocytosis. Other features include a low reticulocyte count, leukopenia with neutropenia, increased numbers of hypersegmented neutrophils (1% neutrophils with ≥6 nuclear lobes or 5% neutrophils with ≥5 nuclear lobes; this is the earliest feature of cobalamin deficiency), moderate thrombocytopenia, and occasionally the presence of large platelets.

2. Biochemical and immunologic studies: Low serum cobalamin levels (note that the proportion of false-positive and false-negative results is high). Supplementary findings include increased serum or plasma homocysteine and/or methylmalonic acid (MMA) levels (>400 nmol/L), features of moderate hemolysis (increased serum lactate dehydrogenase levels, decreased haptoglobin levels, minor elevations of unconjugated bilirubin levels), and increased serum iron levels. In patients with pernicious anemia autoantibodies against parietal cells and intrinsic factor are present.

3. Bone marrow biopsy (usually not needed) reveals hypercellular bone marrow with megaloblastic changes, features of dyserythropoiesis and intramedullary hemolysis, multiple giant metamyelocytes and bands, hypersegmented granulocytes, and large multinucleated megakaryocytes.

4. Gastroscopy: Features of atrophic gastritis in patients with pernicious anemia.

5. Response to treatment: Prompt normalization of hematologic parameters after parenteral administration of vitamin B12 supports the diagnosis of cobalamin deficiency. Care should be exercised to ensure that coexisting B12 and folate deficiency are not present, as treatment of only folate deficiency can exacerbate underlying B12 deficiency and worsen neurologic disease.

The Schilling test is of historical interest as a test for B12 absorption; it may still be available in some jurisdictions but is no longer available in most countries. It tests for the ability to absorb radiolabeled vitamin B12.

Diagnostic Criteria

Diagnosis is based on the clinical features, low serum cobalamin levels, and/or elevated MMA levels.

Differential Diagnosis

Folate deficiency, other types of anemia associated with dyserythropoiesis (sideroblastic anemia, myelodysplastic syndromes), other conditions associated with RBC macrocytosis (alcohol dependency, cirrhosis, purine inhibitors [methotrexate, mercaptopurine, cyclophosphamide, zidovudine, trimethoprim], hydroxyurea, hypothyroidism, reticulocytosis).

Treatment Top

1. Parenteral or oral cyanocobalamin:

1) IM or deep subcutaneous cyanocobalamin 1 mg daily for 7 to 14 days followed by administration once a week until the resolution of anemia (4-8 weeks). Maintenance treatment (especially in patients with neurologic manifestations) includes lifelong IM administration of 1 mg of cyanocobalamin once per month. In cases of severe deficiency, the first dose of parenteral cobalamin can be associated with severe symptomatic hypokalemia reported to be associated with cardiac dysrhythmia and death.

2) The efficacy of high-dose oral cyanocobalamin (1-2 mg/d) is the same as in parenteral treatment. A replacement oral dose as low as 1 mg/mo may be enough once stability is achieved. If oral therapy is used, the B12 level should be assessed to ensure adequate absorption.

2. Symptomatic anemia: Transfusion of packed red blood cells.

Prognosis Top

Treatment leads to the resolution of anemia and hematologic abnormalities. An increase in reticulocyte counts and decrease in mean corpuscular volume are observed after 4 to 5 days of treatment. Hemoglobin levels, hematocrit values, and RBC counts start to increase as early as after 7 days of treatment and return to normal after ~2 months of treatment. Peripheral neuropathy may partially improve (usually within 6 months), but demyelination of the spinal cord is irreversible. Pernicious anemia is associated with a 2- to 3-fold increase in the risk of gastric adenocarcinoma.

Prevention Top

Prophylactic administration of cyanocobalamin may be necessary in patients after gastric surgery. People with diets deficient in animal proteins should consider prophylactic supplements.

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