Vitamin B12 Deficiency

Etiology

Vitamin B12 deficiency has 4 primary etiologies:

1. Autoimmune: Pernicious anemia is an autoimmune condition in which antibodies to intrinsic factors are produced. Anti-intrinsic factor antibodies bind to and inhibit the effects of intrinsic factors, resulting in an inability of B12 to be absorbed by the terminal ileum. 
2. Malabsorption: Parietal cells in the stomach produce intrinsic factors; therefore, any patient with a history of gastric bypass surgery may be at risk for developing a B12 deficiency because their new alimentary pathway bypasses the site of intrinsic factor production. In patients with normal intrinsic factor production, any damage to the terminal ileum, such as surgical resection due to Crohn's disease, will impair the absorption of B12 and lead to a deficiency. Other damage to the small intestine, such as inflammation from celiac disease or infection with the tapeworm Diphyllobothrium latum, may also result in a B12 deficiency.
3. Dietary insufficiency: Vitamin B12 is stored in excess in the liver; however, patients who have followed a strict vegan diet for approximately 3 years may develop a B12 deficiency from a lack of dietary intake.
4. Toxin exposure: Exposure to nitrous oxide can cause vitamin B12 deficiency and neurologic symptoms.

Epidemiology

The epidemiology of vitamin B12 deficiency varies based on the etiology. In the general population, some studies have shown that among patients with anemia, approximately 1% to 2% is due to B12 deficiency. Other studies have shown that among patients with clinical macrocytosis (defined as a mean corpuscular volume, MCV, >100), 18% to 20% were due to B12 deficiency. Vitamin B12 deficiency is more common in older patients, regardless of the cause. B12 deficiency due to pernicious anemia is more common in people of Northern European ancestry. The incidence of pernicious anemia is lower in people of African descent or people from other areas of Europe.[4][5]

Pathophysiology

In healthy patients, dietary vitamin B12 binds to a protein called R-factor, which is secreted from salivary glands. Once the complex arrives at the small intestine, B12 is cleaved from R-factor by pancreatic enzymes, allowing it to bind to a glycoprotein called intrinsic factor, which is secreted by gastric parietal cells. The newly formed complex of B12 and intrinsic factor can then bind to receptors on the ileum, which allows for absorption of B12. Once absorbed, B12 is involved in metabolic pathways important in both neurologic and hematologic functions. If B12 cannot be absorbed, regardless of the etiology, many impairments may occur.

Vitamin B12 is a cofactor for the enzyme methionine synthase, which is used in the conversion of homocysteine to methionine. As a byproduct of this reaction, methyltetrahydrofuran (methyl-THF) is converted to THF, which is converted to intermediates used in the synthesis of pyrimidine bases of deoxyribonucleic acid (DNA). In B12 deficiency, homocysteine cannot be converted to methionine, and thus, methyl-THF cannot be converted to THF. As a result, homocysteine levels accumulate, and pyrimidine bases cannot be formed, slowing down DNA synthesis and can cause megaloblastic anemia. The anemia then leads to symptoms such as fatigue and pallor that are commonly seen in patients with B12 deficiency. The impaired DNA synthesis causes problems for other rapidly proliferating cell lines, such as polymorphonuclear leukocytes (PMNs). Thus, B12 deficiency characteristically results in the formation of hypersegmented neutrophils.

Vitamin B12 is also used as a cofactor for the enzyme methylmalonyl-CoA mutase, which converts methylmalonyl-CoA to succinyl-CoA. In patients with B12 deficiency, methylmalonic acid (MMA) levels will accumulate, as it cannot be converted to succinyl-CoA. A hypothesis states that elevated levels of MMA, along with elevated levels of homocysteine, contribute to myelin damage, accounting for the neurologic deficits, such as neuropathy and ataxia, seen in these patients. The damage to the myelin results in a condition known as subacute combined degeneration of the spinal cord (SCDSC). This condition affects various parts of the spinal cord, including the dorsal columns, the lateral corticospinal tracts, and the spinocerebellar tracts, resulting in a loss of proprioception, ataxia, the development of peripheral neuropathy, and dementia.[6][7]

History and Physical

A thorough evaluation of vitamin B12 deficiency should include a complete history and physical with an increased emphasis on gastrointestinal (GI) and neurologic findings. B12 deficiency can manifest as macrocytic anemia, and thus, the presenting symptoms often include signs of anemia, such as fatigue and pallor. Due to the increased hemolysis caused by impaired red blood cell formation, jaundice may also be a presenting symptom. Therefore, a thorough dermatologic exam may also be helpful. Other presenting complaints may include peripheral neuropathy, glossitis, diarrhea, headaches, and neuropsychiatric disturbances. When obtaining a complete GI history, it is important to look for a past medical history of celiac disease or Crohn disease. Any surgical history of gastrectomy or bowel resection, especially resection of the ileum, should increase suspicion of B12 deficiency. In addition, a dietary history may reveal that a patient has switched to a strict vegan diet within the last few years, which would also increase suspicion of B12 deficiency. In more severe cases, the disease process can progress to involve the nervous system. As mentioned above, SCDSC can result from B12 deficiency, causing damage to various segments of the spinal cord. A complete neurologic exam should evaluate for dementia, peripheral neuropathy, ataxia, and a loss of proprioception. A mental status exam may also be useful to evaluate any neuropsychiatric changes.

Evaluation

In patients with suspected B12 deficiency, initial lab tests should include a complete blood count (CBC) with a peripheral smear and serum B12 and folate levels. In cases where the diagnosis is still unclear after initial testing, other lab tests, such as MMA and homocysteine levels, are available. In patients who are deficient in B12, the CBC often shows anemia, which manifests as a decrease in both hemoglobin and hematocrit. In addition, the mean corpuscular volume (MCV), which measures the size of red blood cells, would be increased to a level greater than 100. This is consistent with a diagnosis of macrocytic anemia. A peripheral blood smear would show hypersegmented neutrophils, with a portion of the neutrophils having greater than or equal to 5 lobes. 

Serum B12 and folate levels also should be obtained. Folic acid deficiency also presents as macrocytic anemia and is often confused with B12 deficiency. Ordering serum levels of both B12 and folate can help differentiate between the two disease processes. A serum B12 above 300 pg/mL is interpreted as normal. Patients with B12 levels between 200 and 300 pg/mL are considered borderline, and further enzymatic testing may be helpful in diagnosis. Patients with B12 levels below 200 pg/mL are considered deficient. However, a low serum B12 level does not determine the etiology of the deficiency. If the etiology is uncertain, further testing should be done to investigate. Further enzymatic testing should be performed in patients with borderline B12 levels (200 to 300 pg/mL). As described, B12 deficiency results in the accumulation of MMA and homocysteine. Thus, serum levels of MMA and homocysteine should both be elevated in cases of B12 deficiency. These lab values can also help to distinguish B12 deficiency from folate deficiency, in which homocysteine levels are elevated but MMA levels are normal. 

After a B12 deficiency confirmation, the etiology must be addressed. Often, a surgical history, including a gastrectomy, resection of the terminal ileum, or gastric bypass, will be the cause. If there is no pertinent surgical history, an appropriate GI workup for causes of malabsorption, such as Crohn or celiac disease, should be performed. In other cases, a history of adherence to a strict vegan diet may be the source. If both the GI and dietary workup are negative, then the cause is likely autoimmune. Blood tests for serum levels of anti-intrinsic factor antibodies may lead to the diagnosis of pernicious anemia. Classically, a test known as the Schilling test was used to diagnose pernicious anemia; however, this test is no longer performed. It involved having the patient orally ingest radiolabeled B12. If the patient excreted the radiolabeled B12 in the urine, it indicated normal B12 absorption. A problem with B12 absorption prevents radiolabeled B12 excretion into the urine, indicating a cause of malabsorption or pernicious anemia.[8][9][10]

Treatment / Management

Treatment of vitamin B12 deficiency involves repletion with B12. However, depending on the etiology of the deficiency, the duration and route of treatment vary. In patients who are deficient due to a strict vegan diet, an oral supplement of B12 is adequate for repletion. In patients with a deficiency in intrinsic factors, either due to pernicious anemia or gastric bypass surgery, a parenteral dose of B12 is recommended, as oral B12 will not be fully absorbed due to the lack of intrinsic factors. A dose of 1000 mcg of B12 via the intramuscular route is recommended once a month. In newly diagnosed patients, 1000 mcg of B12 is given intramuscularly once a week for four weeks to replenish stores before switching to once-monthly dosing. Studies have shown that at doses high enough to fully saturate intestinal B12 receptors, oral B12 is also effective, despite a lack of intrinsic factors. In anyone at risk of developing a B12 deficiency, such as patients with Crohn disease or celiac disease, routine monitoring of B12 should be performed. If the severity of the disease worsens and B12 levels begin to decline, treatment is then started. However, prophylactic treatment before B12 levels fall is not indicated.[11][12][13]

Differential Diagnosis

The differential diagnosis includes the following:

• Lead toxicity
• Syphilis
• HIV myelopathy
• Multiple sclerosis

Prognosis

For patients who are promptly treated with vitamin B12, the prognosis is good. In general, younger patients have better outcomes compared to older individuals. The best response is obtained in people with the absence of severe neurological deficits.

Complications

Complications can include the following:

• Heart failure due to anemia
• Severe disabling neurological deficits
• Risk of gastric cancer
• Risk of developing an autoimmune disorder like type 1 diabetes, myasthenia gravis, Hashimoto disease, or rheumatoid arthritis