Folate Deficiency

Folate is also known as Vitamin B9. It is one of a group of important vitamins involved in cell metabolism. Folate plays a critical role in the synthesis of DNA, RNA and proteins. Deficiency can therefore cause impairment of cell division and an accumulation of possibly toxic metabolites, e.g. homocysteine. Along with Vitamin B12, folate is important for regulating the manufacture of red blood cells. 1

The synthetic form of folate is folic acid, which converts to folate in the body. Because folic acid is more easily absorbed by the body, it is the form most commonly used in supplements and fortified foods.

Many plants, particularly green leafy vegetables, and animal products contain folate. Thus, most healthy people absorb sufficient folate from their diets to avoid deficiency, but in some cases the body may increase demand. If supplementation doesn’t occur, this may lead to deficiency.

Folate deficiency is most commonly found in pregnant and lactating women, people with chronic conditions of the gastrointestinal tract, people following restricted diets due to weight-loss regimes or medical conditions, people with alcohol dependence and people more than 65 years of age. 2

Folate deficiency will not go away on its own. Treatment is required and may involve dietary changes and/or oral supplements and treatment of underlying causes, if any are present. If left untreated, folate deficiency may result in folate deficiency anemia, which can cause severe complications. 3

Common symptoms of folate deficiency can include: 2 4

• Tiredness, fatigue and lethargy
• Muscle weakness
• Neurological signs, such as a feeling of pins and needles, tingling, or burning, or peripheral neuropathy, i.e. a numbness in the extremities
• Psychological problems, such as depression, confusion, memory problems, problems of judgment and understanding
• Gastrointestinal signs, such as nausea, vomiting, abdominal pain, weight loss and diarrhea
• Headache and dizziness
• Pallor
• Shortness of breath.

Headache, dizziness, pallor and shortness of breath are also symptoms of anemia. Anemia, particularly megaloblastic anemia, is often the first sign that there is an underlying folate deficiency, and doctors will usually test for folate and Vitamin B12 deficiencies when they encounter anemia.

Less common symptoms of folate deficiency are: 2

• Fast heartbeat (tachycardia)
• Fast breathing (tachypnoea)
• Exfoliative dermatitis, a condition which makes the skin red and scaly
• Heart murmur
• Painful swallowing
• A sore tongue (glossitis) and mouth ulcers
• Petechiae
• Angular stomatitis (fissures in the corners of the mouth).

In children with congenital malabsorption disorders, which are rare, neurological problems might also be present.

Diagnosis is based on evaluation of symptoms and blood tests. Although there is no official medical consensus of what level of folate in blood serum indicates a deficiency, most practitioners agree that a level of less than seven nanomoles per liter (7nmol/L) is problematic. Below that level, the risk of megaloblastic anemia is much higher. 3 If a blood test reveals anemia, this will lead to further evaluation of the possible causes, including analyzing serum folate levels. Elevated homocysteine levels can also indicate a folate deficiency and can therefore be part of the laboratory testing.

The process of diagnosing a folate deficiency involves the exclusion of other possible causes of the symptoms. In cases where anemia is suspected, other possible causes of anemia, for example iron deficiency, vitamin B12 deficiency, chronic disease and others, must be excluded.

Physicians will evaluate the affected person’s diet for signs of insufficient intake, such as might accompany vegan diets, poor diets, or “fad” diets. Often, people with this condition present with a history of alcohol intake which contributes to a poor diet. Other affected people may be pregnant or lactating. Certain drugs, such as anticonvulsants, can also cause this type of deficiency.

Folate deficiency has a number of potential causes. Most healthy people absorb sufficient folate from their diets to avoid deficiency, but in some cases the body may increase demand, which, if supplementation doesn’t occur, may lead to deficiency. In other cases, the body may be unable to absorb enough folate, due to low intake or excessive excretion.

Causes of folate deficiency include: 1 2 3 5

• Low dietary intake due to medically restricted diets such as those followed by people with phenylketonuria or due to fad diets concentrating on foods that do not contain enough folate. Infants who are fed unfortified goat’s milk will also experience folate deficiency, as folate is not naturally present in goat’s milk.
• Malabsorption, which can be due to age, liver problems or gastrointestinal problems causing chronic diarrhoea, such as sprue, celiac disease or inflammatory bowel disease. Other causes of malabsorption are pancreatitis, bariatric surgery and extensive surgery involving the large or small intestine. Malabsorption is also a risk for people who use drugs that interfere with the absorption of folate, such as proton-pump inhibitors, some anticonvulsants such as carbamezapine, phenytoin, valproic acid, and phenobarbitol. 6
• Disorders such as leukaemia, carcinomas and lymphomas,, which increase the body’s demand for folate and may consequently lead to deficiency if folic acid supplements aren’t taken.
• Age, which causes changes in the gastrointestinal systems of people more than 65 years of age. These may lead to reduced absorption and reduced dietary intake.
• Alcohol-related damage to the liver, which affects the way in which folate is stored in the liver and increases the amount of folate excreted in urine. People with alcohol dependence may also have a nutritionally insufficient diet.
• Pregnancy and lactation, which raise the body’s demand for folate considerably due to the growth of new tissue in both mother and fetus. Sufficient folic acid supplementation is crucial for pregnant women, as a deficiency may cause birth defects.
• Smoking or exposure to secondhand smoke. 7
• Renal dialysis, which affects the amounts of homocysteine in the body and therefore increases the amount of folic acid needed.

While folic acid is found in many food and fortified products, some groups of people are more likely to develop a deficiency than others. Pregnant women, people with alcohol use addictions and the elderly are at particular risk. 8

Alcoholism causes physical damage to the body, and one significant element of this is the development of nutritional deficiencies. This is the result of damage to the liver, which uses stored nutrients to process alcohol. Alcohol abuse causes the liver to run out of stored nutrients, causing the body to draw nutrients out of the bloodstream to make up the difference. 9 This can cause deficiencies of Vitamin A, calcium, Vitamin B12 and Vitamin B9, which is also called folic acid or folate.

High alcohol concentrations can also directly destroy B vitamins in the gastrointestinal tract. 8 The body’s ability to process nutrients is further compromised as alcohol damages the liver, pancreas and stomach. The ability of the small intestine to absorb nutrients such as folate is also reduced. 10

Furthermore, some people with alcoholism do not eat balanced diets, leading to low nutrient intake. Folate is one of the most important nutrients affected by excessive alcohol use. Folate deficiency can contribute to the development of alcoholic liver disease. 10

Folic acid is vital during pregnancy, as it is required for the growth and development of the fetus.

In women, pregnancy increases the risk of folate-deficiency-related anemia because of the effect it has on the mother’s circulatory system. During pregnancy, the mother’s blood volume increases, meaning that plasma levels and red blood cell numbers increase. Folate is needed to produce red blood cells, so pregnant women experience an increased demand for folate. 11

In fetuses, folate is crucial for the proper development of the neural tube. Folic acid also prevents oral clefts and congenital heart disease. 11

Ideally, women who are planning to have a baby should begin to supplement with folic acid before they fall pregnant (see below).

It is well-established that folic acid levels can have an affect on a person’s mood, social function and cognitive function, especially among older people. 12 Depression is also common in people with folic acid deficiency. Many elderly people have folic acid deficiencies, because of ageing, poor diets linked to reduced income or absorption problems caused by medication. Some older people also develop an increased demand for folate, for unknown reasons. ref12

Supplementation with B9 for older people may be helpful, and some studies have found that increasing folic acid supplementation in people with low folate levels leads to notable improvements in mood, cognitive function and social functioning.

However, it is not advisable to begin taking folate supplements without consulting a physician. This is important because in elderly people with anemia, supplementing with B9 may cover the effects of B12 deficiencies. 13 For more information on B12 deficiencies, see the FAQs below. If you are concerned that you or a loved one may have a folate deficiency, you can do a free symptom assessment with Ada.

There are several possible health consequences of having folate deficiency. These include:

Megaloblasts are large, poorly-formed red blood cells that form in cases of anemia caused by, among others, folate or B12 deficiencies. Megaloblastic anemia is a result of folate deficiency as well as one of the most easily-identified symptoms: sometimes, a deficiency is only identified when anemia presents. If it results from folate deficiency, this anemia, is treated by taking oral or intravenous folate supplements. 14 For more information on folate-related anemia and B12-related anemia, see FAQs below.

Folic acid is very important in the correct development of cells and is crucial for the correct development of fetuses. Pregnant women and women planning to become pregnant should increase their folic acid intake to 400 micrograms a day.

Women should increase their intake to 5mg a day if they are or wish to become pregnant and are affected by the following factors: 15 If a women is affected by diabetes, celiac disease, a BMI of more than 30 or is treated with drugs that affect folate absorption, additional supplementation must be considered.

Folic acid deficiency in the mother can cause defects in the neural tube, which is the structure that eventually develops into the baby’s spinal cord. Neural tube defects (NTDs) can include spina bifida, caudal regressive (affecting the lowest part of the spine), and cleft palate. Extremely rare, but severe, complications of folic acid deficiency can include anencephaly and encephaloceles, which involve the baby’s skull and brain. 16

In most cases, folate deficiency is relatively easy to correct. In cases where a deficiency has set in due to poor diet or age, taking a folic acid supplement or modifying the diet is sufficient. However, if there is an underlying problem, like alcoholic changes to the liver or a drug interaction or condition causing malabsorption, specialised treatment will be required. The underlying causes of folate deficiency need to be addressed to prevent the problem recurring.

Folate deficiency is relatively easily treated in cases where the deficiency is not severe. However, where it has caused anemia, folic acid supplementation and/or correcting diet alone will not be enough. In women with megaloblastic anemia, vitamin B12 deficiency must be ruled out before any folic acid treatment can begin. If complications have occurred, or if there is an underlying condition or factor causing the folate deficiency, the affected person may have to be referred to one or more of the following kinds of doctor: 2

• Gastroenterologist, a doctor specialising in diseases and disorders of the esophagus, stomach, small intestine, colon and rectum, as well as the pancreas, gallbladder, bile ducts and liver
• Dietitian, a certified expert on diet and nutrition
• Hematologist, a doctor specialising in diseases and disorders of the blood

Folate is readily available in many whole foods, such as: 15

• Leafy green vegetables such spinach, kale, broccoli, cabbage, and brussels sprouts
• Beetroot
• Citrus fruits
• Liver
• Beans and legumes such as peas, pinto, cannellini, or garbanzo beans/chickpeas

Good to know: Liver should be avoided by pregnant women, due to the high levels of Vitamin A it contains. Too much vitamin A can cause birth defects.

In some countries, such as the United States, South Africa, Chile, Canada and Costa Rica, grain cereal products (bread, pasta and breakfast cereals) are fortified with folic acid. 17 This is a major factor in reducing the number of neural tube defects that occur, but it is still recommended that anyone who is at risk of a deficiency, such as pregnant women, should make sure to get 400 micrograms of folate a day. This is especially the case if the following risk factors are present:

• Celiac disease or other intestinal absorption disorders
• Thalassemia or sickle cell anemia; hereditary red blood cell disorders
• Clinical obesity, a BMI of 30 or more.
• Family history of, or partner with a family history of, neural tube defects. In this case, folic acid acts as “insurance.”
• Rapid cell turnover (hemolysis) occuring as a result of chronic hematological disorders 3

Q: How much folic acid should I take every day?
A: The daily need of folic acid differs between adults (200mcg) and people younger than 14 years of age (150-200mcg). It must be emphasized that men, children and women who are not likely to become pregnant obtain a sufficient amount of folate in a healthy diet, containing a wide variety of foods. Pregnant and lactating women need at least 400 micrograms a day and possibly as much as 800mcg. Pregnant and lactating women with diabetes, or a family history of neural tube defects, should consult a specialist for optimum supplementation during pregnancy. 18

Q: How much folic acid is too much?
A: The safe upper limit for daily folate/folic acid intake is 1000 micrograms a day. Beyond this, there might be adverse effects. 19 Not much is known about the long-term adverse effects of exceeding the upper limit, if any. 20 It has been suggested that taking too much folic acid is particularly risky for elderly people, because taking large amounts of B9 can mask the symptoms of a Vitamin B12 deficiency.

Q: Can folic acid deficiency cause diarrhea?
A: Yes, it can. Folic acid deficiency can cause a range of gastrointestinal problems, including diarrhea, stomach pain, and indigestion. Folic acid deficiency can lead to weight loss because of causing lack of appetite.

Q: How does taking extra folate affect a Vitamin B12 deficiency?
A: Vitamin B12 deficiency can cause severe neurological damage. It can also cause megaloblastic anemia. Taking supplemental doses of Vitamin B9 does make it look like the B12 deficiency is being cured, because it can increase the number of red blood cells in the body, which improves the anemia. But it does not cure the deficiency, and the neurological damage caused by the B12 deficiency will continue. It is possible that taking extra Vitamin B9 in cases of Vitamin B12 deficiency can worsen the severity of the B12 deficiency, but this is not known for certain. It is best to consult a physician if there is any possibility of a B12 deficiency. 14

Q: Is folate supplementation safe for people with cancer?
A: It is not known for certain whether supplementation with folic acid is safe for people with cancer. Some studies suggest that folic acid reduces the chance of developing cancer and accelerates the progression of certain types of cancer; other studies suggest the opposite. 12 It is best to consult specialist physicians and/or oncological caregivers before beginning supplementation.

Q: What sort of anemia results from a deficiency of Vitamin B12?
A: The type of anemia that results from a vitamin B12 deficiency is known as pernicious anemia, a type of megaloblastic anemia. Megaloblastic anemia can also be caused by a deficiency of folic acid. In B12-related anemia, low levels of B12 affect the body’s ability to make red blood cells, resulting in anemia.

Q: What causes B12-related anemia, also known as pernicious anemia?
A: In some people, low B12 levels happen because they cannot absorb B12 from food due to a lack of a substance known as intrinsic factor in the stomach. Other causes of low B12 levels include infections, surgery, some medications or diet, all of which can affect the amount of B12 that the body can absorb. 21

B12-related anemia can affect anybody, but is most prevalent among people with English, Irish, Scottish or Scandinavian heritage and people between the ages of 40 and 70. It is as likely to affect men as it is women. 22

Causes of B12-related anemia include: 21

• Celiac disease
• Crohn’s disease
• HIV infection
• Some types of medication for diabetes or epilepsy
• Antibiotics that affect the gut’s bioflora, as bacteria use the B12 before the host can absorb it
• Surgical removal of part of the small intestine
• Alcoholism
• Tapeworm infection, as the parasite uses the B12 before the host can absorb it
• A diet low in B12

Strict vegetarians and vegans are at increased risk of developing B12-related anemia because of their diets. Foods that are rich in B12 are animal products such as beef, fish, eggs and dairy products. 21 B12 anemia can also affect the babies of breastfeeding women who are strict vegetarians or vegans. However, in certain countries, many cereals and grain products are enriched with B12.

Q: What are the symptoms of B12-related anemia?
A: Symptoms of B12-related anemia include:

• Weight loss and loss of appetite
• Increased heart rate
• A painful, smooth, red and slightly swollen tongue
• Low-grade fever
• Weakness
• Clumsiness
• Hearing loss or vision loss
• Tingling in the extremities
• Unsteady gait/walk
• Gastrointestinal symptoms such as constipation, nausea, vomiting, flatulence or heartburn.

If the affected person is experiencing severe abdominal pain, a doctor should be consulted as soon as possible, as this indicates a severe B12 deficiency.

In older people, a B12 deficiency may also cause

• Memory loss
• Irritability
• Personality changes

If you are concerned that you or a loved one might have pernicious anemia/B12-related anemia, Ada is ready to start your symptom assessment.

Q: How does megaloblastic anemia differ from other anemias?
A: Anemia occurs when an individual has too few or deformed red blood cells (erythrocytes). For example, anemia can occur when an individual’s iron levels are too low, e.g. when they are undergoing chemotherapy, or when they have kidney disease.

Megaloblastic anemia is also known as Vitamin B12-related anemia, folate-related anemia, or macrocytic anemia. It occurs when the body produces short-lived, large, poorly-developed red blood cells. 15 These blood cells cannot move out of the bone marrow where they develop, due to their shape. As a result, there are too few red blood cells in the blood, leaving the affected person feeling weak and fatigued.

Other types of anemia are hemolytic anemia, a subtype of hemolytic anemia known as sickle-cell anemia, and aplastic anemia. Hemolytic anemia can be inherited, as in the case of thalassemia or glucose-6 phosphate dehydrogenase deficiency. It can also be caused by autoimmune disorders, infections or leaky heart valves. It occurs when red blood cells break up in the blood vessels or the spleen. 23 Sickle-cell anemia is hereditary and causes rigid red blood cells that do not readily flow through the blood vessels. Aplastic anemia occurs when the bone marrow stops making enough red blood cells, often when the body’s immune system attacks it.

For more information on anemia, see this resource on anemia. If you are worried that you or a loved one might have anemia, Ada is ready to start your free symptom assessment.