B12 and folate (also known as folic acid or vitamin B9) are nutrients that cannot be produced in the body and must be supplied by the diet. A healthy body typically has enough vitamin B12 stored to last three to five years but does not store a significant amount of folate. A B12 and/or folate deficiency reflects a chronic shortage of one or both of these vitamins.
In the U.S., B12 and folate deficiencies are not common in healthy adults because the body can store sufficient amounts for a period of time. Most adults eat enough foods that contain or are supplemented with these vitamins to meet their daily requirements. There are, however, people at risk of deficiency, such as:
- The elderly
- People with intestinal conditions that prevent them from absorbing enough of the vitamins
- Heavy alcohol drinkers
- Vegetarians and vegans
- Pregnant women, who need increased amounts of these vitamins
- People with long-term use of certain medications
The prevalence of a B12 deficiency in people under age 60 is estimated to be about 6% in the U.S. and United Kingdom and nearly 20% in people over age 60. B12 and folate deficiencies and their associated signs and symptoms can take months to years to manifest in adults. Infants and children will show signs of deficiency more rapidly because they have not yet had time to store sufficient amounts.
Over time, a deficiency in either B12 or folate can lead to a condition in which red blood cells are enlarged (macrocytic anemia). This production of fewer but larger red blood cells decreases the blood's ability to carry oxygen. People with anemia may be weak, light-headed, and short of breath. Megaloblastic anemia, a type of macrocytic anemia, is characterized by the production of fewer but larger RBCs in addition to some cellular changes in the bone marrow. Other laboratory findings associated with megaloblastic anemia include decreased white blood cell (WBC) count, red blood cell (RBC) count, reticulocyte count, and platelet count.
A deficiency in B12 can also result in varying degrees of neuropathy or nerve damage that can cause tingling and numbness in the person's hands and/or feet. In severe cases, mental changes that range from confusion and irritability to dementia may occur.
Pregnant women need increased folate for proper fetal development because of the added stress of rapidly growing fetal cells. A folate deficiency during pregnancy, especially in the early weeks when a woman might not know she is pregnant, may lead to premature birth and neural tube birth defects (NTDs) such as spina bifida in the child. To help prevent NTDs, the Food and Drug Administration mandated increased folate supplementation of grain products a number of years ago, which led to about a 50% decrease in neural tube defects in the U.S. Even so, it can be difficult sometimes to get enough folate from foods, so it is recommended that all women who may become pregnant take 400 micrograms of folate every day.
The initial signs and symptoms associated with B12 and folate deficiencies may be subtle and nonspecific. They may be related to the effects of megaloblastic anemia, nerve damage, and/or gastrointestinal changes. Affected people may experience a variety of mild to severe signs and symptoms that can include:
- Diarrhea, constipation
- Fatigue, muscle weakness
- Loss of appetite
- Pale skin
- Rapid heart rate, irregular heartbeats
- Shortness of breath
- Sore or smooth tongue and mouth
- Tingling, numbness, and/or burning in the feet, hands, arms, and legs (with B12 deficiency)
- Confusion or forgetfulness
- Paranoia, irritability
There are a variety of causes of B12 and/or folate deficiencies. They include: Insufficient dietary intake B12 is found in animal products such as red meat, fish, poultry, milk, and eggs. Folate, also called folic acid or vitamin B9, is found in leafy green vegetables, citrus fruits, dry beans, yeast, and vitamin- fortified cereals.
The human body stores several years' worth of B12 in the liver. Since a variety of foods consumed by Americans contain B12, a dietary deficiency of this vitamin is extremely rare in the U.S. It may be seen, for example, in people with generally poor nutrition or malnutrition, in vegans who do not consume any animal products, including milk and eggs, and in breastfed infants of vegans. In adults, dietary deficiencies do not usually cause symptoms until stores of the vitamins within the body have been depleted. Deficiencies in children and infants, however, show up fairly quickly since they have not had time to store as much of the vitamins as adults.
Folate deficiency used to be a common, but in 1997 the U.S. government mandated supplementation of cereals, breads, and other grain products with folic acid. Folate is a water-soluble vitamin, thus is not stored in fat tissues. On average, the total body amount of folate available is about 15 to 30 mg, half of which is stored in the liver and the rest in blood and other tissues. Because folate is stored in smaller quantities than B12, folate must be consumed more regularly than B12.
Malabsorption Both B12 and folate deficiencies may be seen in people who have conditions that interfere with absorption of the vitamins in the small intestine. Vitamin B12 absorption occurs in a series of steps. B12 is normally broken down from food protein by stomach acid and pepsin. It is then processed in the small intestine, where it binds to intrinsic factor (IF), a protein made by parietal cells in the stomach. This B12-IF complex is then absorbed by the small intestine, bound by carrier proteins (transcobalamins), and enters the circulation. If a disease or condition interferes with any of these steps, then B12 absorption is impaired.
Some examples of these conditions include:
- Pernicious anemia, an autoimmune condition that affects the absorption of B12 and is the most common cause of B12 deficiency. Intrinsic factor is made by parietal cells that line the stomach and is needed for B12 absorption. In pernicious anemia, inflammation damages the parietal cells, resulting in little or no production of intrinsic factor, thus preventing the intestines from absorbing B12. With insufficient B12, the body produces enlarged but fewer red blood cells. Because of the larger than normal red blood cells, this is often referred to as megaloblastic anemia, a type of macrocytic anemia. Celiac disease is an autoimmune disease caused by an inappropriate immune response to gluten, a protein found in wheat, rye, and barley.
- Inflammatory bowel disease, including Crohns disease and ulcerative colitis
- Bacterial overgrowth or the presence of parasites in the intestines Reduced stomach acid production; stomach acid is necessary to separate B12 from the protein in food. This is the most common cause of B12 deficiency in the elderly and in individuals on drugs (H2 receptor antagonists or proton pump inhibitors) that suppress gastric acid production. Surgery that removes part of the stomach (and the parietal cells) or the intestines may greatly reduce absorption of nutrients. This is a concern that is considered when gastric by-pass procedures are performed. Chronic pancreatitis, long-lasting inflammation in the pancreas most commonly caused by gallstones or long-term alcohol abuse
Increased need for folate and/or B12:
- During pregnancy, there is increased cell production and DNA synthesis, thus an increased need for folate. Prenatal vitamin supplements that include folic acid are recommended prior to getting pregnant and during the pregnancy, which may help prevent certain birth defects. Women of childbearing age should strongly consider proper diets and/or supplements to ensure daily intake of 400 mcg/day because neural tube defects can develop in the first few weeks of pregnancy before a woman realizes she is pregnant. (For more details, read the article on Neural Tube Defects.). If a woman has a folate deficiency prior to pregnancy, it will be intensified during the pregnancy and may lead to premature birth and neural tube defects in the child. People with cancer that has spread (metastasized) or with a chronic hemolytic anemia such as sickle cell disease have an increased need for folate.
- Anti-seizure medications such as phenytoin can decrease folate by blocking folate absorption.
- Methotrexate, an anti-cancer drug, affects body metabolism and use of folate.
- Heavy alcohol drinking and alcoholism can cause B12 and/or folate deficiencies through a combination of poor nutrition, malabsorption issues, and a decrease in the amount of B12 released from dietary proteins. Some drugs can cause B12 deficiency. For example, the diabetes drug metformin prevents B12 from being absorbed, while omeprazole (an acid reflux drug also known as Prilosec) reduces gastric acids and prevents B12 release from food. A genetic variant (mutation) in the methylenetetrahydrofolate reductase gene (MTHFR) impairs folate activity. About 25% Hispanics, 10% Caucasians, and 1% African Americans may have this abnormality.
Screening people for a B12 deficiency isn't recommended unless they have high risk factors. Laboratory testing may be used to detect a vitamin deficiency if you are at risk, determine its level of severity, establish an underlying cause of symptoms, or to monitor the effectiveness of treatment. Tests ordered to diagnose or monitor B12 and folate deficiencies:
- CBC - the complete blood count (CBC) is a group of tests ordered routinely to evaluate the health of blood cells. The CBC determines the number of white blood cells (WBCs) and red blood cells (RBCs), hemoglobin level, hematocrit, platelet count, and mean corpuscular volume (MCV; reflects size of the RBCs). Macrocytic/ megaloblastic anemia and large red blood cells are associated with a vitamin B12 or folate deficiency and are often initially detected during a routine CBC. In addition, abnormal physical characteristics of some of the cells are identified that are consistent with these deficiencies. With both B12 and folate deficiencies, the amount of hemoglobin, the hematocrit, RBCs, platelets, and WBCs may be decreased. B12 blood level—if low, a deficiency is indicated, but it does not identify the cause. For example, conditions that impair intrinsic factor (IF) production may be a cause, resulting in the malabsorption of B12. B12 testing may also be ordered to monitor the effectiveness of treatment. Folate level—either serum or RBC folate levels may be tested; if either is low, it indicates a deficiency. The tests may also be ordered to monitor the effectiveness of treatment. However, some health organizations recommend against measuring folate levels. Rather, they recommend simply treating the rare patient who has a deficiency with folate supplements. Methylmalonic acid (MMA)—if B12 is low, MMA is generally high. This test may be ordered to help detect mild or early B12 deficiency.
- Homocysteine - this test is seldom ordered but may be elevated in both B12 and folate deficiency.
Tests ordered to help determine the cause of a B12 deficiency:
- Intrinsic factor antibody—the antibody prevents intrinsic factor from carrying out its function, that is, to carry vitamin B12 and allow B12 to be absorbed at a specific segment of the small intestine. Parietal cell antibody—this is an antibody against the parietal cells that produce intrinsic factor. This antibody can disrupt the production of intrinsic factor and is present in a large percentage of those with pernicious anemia, but it may also be seen in other autoimmune disorders. Gastrin—a hormone that regulates the production of acid in the stomach during the digestive process. Increased gastrin is sometimes seen in pernicious anemia.
Treatment for B12 and folate deficiencies frequently involves taking supplements, which may be long-term or lifetime, depending on the underlying cause. People who lack intrinsic factor or have conditions causing general malabsorption require injections of B12. Additionally, folate is given as an oral supplement.
It is generally recommended that women of childbearing age consider taking folic acid supplements. All pregnant women should take folic acid supplements to ensure that they have a sufficient store for normal fetal development and to prevent neural tube defects.
Individuals deficient in both B12 and folate will need to take supplements containing both vitamins. If someone with a B12 deficiency only takes folic acid supplements, the macrocytic anemia may be resolved but the underlying neuropathy caused by the B12 deficiency will persist. Appropriate treatment should resolve symptoms but may not reverse all of the nerve damage.