Vitamin B12 is found in meats and dairy. The minimum daily requirement is 6 – 9 mcg per day. The body can store up to 5,000 mcg (half in the liver) – meaning it takes years to develop vitamin b12 deficiency after the patient stops consuming and/or absorbing b12.
Causes include pernicious anemia, gastrectomy, gastritis, intestinal disorders, as a medication side effect, inadequate intake, alcoholism, HIV infection, and hereditary causes.
Pernicious anemia is an autoimmune process. There are antibodies directed against gastric parietal cells in 90% of patients. Antibodies also attack gastric intrinsic factor in up to 70% of patients – 95% specific for pernicious anemia.
The anti-intrinsic factor antibodies work in two ways: blocking b12 to intrinsic factor and by blocking the b12-intrinsic factor complex to ileal receptors. Both mechanisms block the absorption of b12.
Gastritis and gastrectomy lead to reduced amounts of gastric acid and pepsin and atrophy of the mucosa that prevents the release of b12 for proper absorption. There’s a possible link between h-pylori infection and low b12 levels.
B12 deficiency is a common finding in those over 65 years of age – even if there isn’t any evidence of anemia. Pernicious anemia most commonly occurs between the ages of 40-70, but can be seen in patients under 30.
Medications such as PPIs, cimetidine, and metformin can all lead to B12 deficiency. B12 deficiency in patients taking metformin can be corrected with supplemental calcium.
Weight loss (10-15 lbs) and a smooth tongue (loss of papillae) is seen in up to half of patients. Classically the tongue will be painful and beefy red.
Patients present with neurological changes such as paresthesias, numbness, weakness, loss of dexterity, impaired memory (treatable cause of dementia), and personality changes. Neuropathy is symmetrical and affects the lower extremities more so than the upper extremities.
Paresthesias and ataxia with loss of vibration and position sense is initially seen. Paresthesias are most common – but any neurological symptoms can be seen. Be on the lookout for a patient who has a recent loss of mental capabilities.
Symptoms occur because of myelin degeneration and loss of nerve fibers in the dorsal and lateral columns of the spinal cord
Patients may have a positive Romberg sign and/or positive Lhermitte’s sign.
Romberg sign:the standing patient is asked to close his or her eyes. A loss of balance is interpreted as a positive Romberg’s test.
Lhermitte’s sign: shock-like sensation that radiates to the feet during neck flexion
Copper deficiency can present almost identical to b12 deficiency and should be included in the differential.
B12 deficiency is also associated with increased risk for osteoporosis and fracture.
Lastly, if the patient is anemic – they will have anemic symptoms. Symptoms are a result of decreased oxygen delivery to tissues. All types of anemia will have the same core symptoms: fatigue, dyspnea on exertion, and palpitations.
Classically we see segmented neutrophils and macrocytosis on peripheral smear. We can also see elevated iron, indirect bilirubin, and LDH – with low levels of haptoglobin. A normal to low reticulocyte count is seen.
Keep in mind, hypersegmented neutrophils can also be seen in iron deficiency. But, if present in the absence of anemia, this should clue you into b12 deficiency. If there is concomitant iron deficiency or thalassemia, the MCV can be normal.
It’s important to remember that b12 deficiency can be seen in the absence of anemia (normal hgb/hct).
Increased homocystein levels can be seen due to the fact that b12 is required for the metabolism of homocystein to methionine.
Finally, b12 deficiency can lead to pancytopenia – decreased RBC, WBC, and platelets.
Diagnosis is made with a decreased vitamin b12 level. The problem is labs use different methods and there are different ranges of normal.
B12 levels can fall during pregnancy and in those taking oral contraception pills – but this does not indicated a deficiency. Up to 5% of patients with a true deficiency can have normal b12 levels. High levels of IF antibodies can lead to falsely elevated levels of serum b12. So, if suspecting this disease it would be wise to also draw IF antibodies.
If the diagnosis is unsure and the patient has a low normal b12 level – then draw an MMA (more sensitive than serum b12 level) and a homocystein level. Elevated MMA and homocystein levels will be seen due to decreased metabolism.
If pernicious anemia is suspected draw IF antibodies and anti-parietal cell antibodies. Other signs to look for are elevated gastrin levels and low pepsinogen 1 levels.
The schilling test is taught classically – but is rarely used clinically.
Don’t forget to rule out folic acid deficiency as well in these patients. The peripheral smear can present the same – but the key difference here is that folic acid deficiency will not cause neurological symptoms and it will not have an increased mma (will have increased homosyteine levels).
Treatment consists of 1000 mcg of b12 IM once a day for one week, followed by 1000 mcg once a week for 4 weeks. If the b12 deficiency is due to irreversible cause – then continue IM injections once a month for the remainder of the patients life.
Oral treatment can also be used as a substitute at doses of 1000 – 2000mcg/day after levels have been restored by parental administration. This still holds true for patients who lack IF. But, if the patient continues to have neurological symptoms – parental therapy is preferred.
Pure vegetarians, vegans, or those on a Mediterranean diet should have supplementation. This is especially true for patients who are pregnant and for those who plan on breast feeding as the newborn will be at even higher risk for developing b12 deficiency.
Elevated levels of iron, indirect bilirubin and LDH will begin to correct itself after a few days of parental therapy. Reticulocytosis begins a few days after administration – but the hemoglobin will take at least 10 days to correct itself and takes up to 2 months for normalization.
Neurological symptoms improve after 3 months but can take up to 12 months for resolution – depending on the extent and duration of vitamin b12 deficiency.
Patients with pernicious anemia are also at increased risk for GI malignancies. So, monitoring is prudent in this population.
Keep in mind – if you treat b12 deficiency with folate, this will fix hematological changes, but will worsen neurological symptoms. Whenever working up megaloblastic anemia, make sure you identify the correct cause. If you’re unsure – treat with both.