Folate deficiency pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Larabe Farrukh

Pathophysiology

• Folate deficiency can occur when the body's need for folate is increased, when dietary intake or absorption of folate is inadequate, or when the body loses more folate than it acquires from the diet.
• Certain medications (e.g Anticonvuslants, Methotrexate, Sulfasalazine) can also interfere with the folate metabolism in our body.
• The deficiency is more common among pregnant women, infants, children, and adolescents.
• Poor diet and chronic alcoholism is also an important cause of folate deficiency.

• Moreover, a defect in homocysteine methyltransferase or a deficiency of cobalamine (B-12) may lead to "folate trap".
• In vitamin B12 deficiency, the utilization of Methyl THF in the B-12 dependent methylation of homocysteine to methionine is impaired.
• THF is converted to methyl-THF which cannot be further metabolized, and serves as a sink of THF that leads to a subsequent deficiency in folate.
• Thus, a deficiency in B-12 can generate a large pool of methyl-THF that is unable to undergo reactions and resembles folate deficiency.
• Folate is absorbed in the small intestine, mainly in the Jejunum, after binding to specific receptor proteins.
• Inflammatory or degenerative changes in the small intestine, such as Crohn's disease, chronic enteritis, Celiac disease, may reduce the folate uptake, which gives rise to folate deficiency.

Physiology

In the human body folic acid serves a number of functions which include the following :

• Production and maintenance of new cells
• DNA and RNA synthesis
• Carrying one-carbon groups for various methylation reactions
• Preventing changes to DNA, therefore, for preventing cancer

Dietary sources

• Folate naturally occurs in a variety of foods, including dark green leaf vegetables, fruits , nuts, soybeans, dairy products, poultry, eggs, seafood, grains, and some beers.
• Avocado, beetroot, spinach, liver, yeast, asparagus, kale, and Brussels sprouts are among the foods that contain the highest levels of folate.
• Folate found in food is susceptible to high heat, UV light and may also be susceptible to damage by oxidation.
• Folic acid is also added to grain products and these fortified products make up a significant source of the population's folate intake.
  • For example enriched flour and fortified rice typically contain folate. In adults, normal total body folate is between 10,000–30,000 micrograms (µg) with blood levels of greater than 7 nmol/L (3 ng/mL).

Absorption and Bioavailability

• Folates exist as polyglutamates in the diet and need to be enzymatically converted into monoglutamate forms by folate reductase. This takes place in the jejunum where the absorption of folate also occurs. Natural folates are quite unstable and they lose their vitamin activity during food processing. In vegetables the folates can be destroyed by cooking and in grains/cereals folates can be broken down during milling and baking.

• Folate itself is not biologically active, but is converted into dihydrofolate, by the enzyme dihydrofolate synthetase, in the liver. This is then converted into tetrahydrofolate (THF) by dihydrofolate reductase.Tetrahydrofolate is converted into 5,10-methylenetetrahydrofolate by serine hydroxymethyltransferase. Tetrahydrofolate and its methylated forms then play a crucial role as methyl donors in different reactions that occurthroughout the body.

• Absolute folate deficiency is usually associated with dietary insufficiency but may it also be caused by impairment in the folate absorption. This can occur due to gastrointestinal diseases or certain genetic defects that impair the absorption in the gastrointestinal tract. Other causes may include mutations causing impaired activity of the enzymes involved in folate metabolism. Low levels of blood folate can lead to increased plasma homocysteine, impaired DNA synthesis and DNA repair and may promote the development of some forms of cancers as well.

Causes

Some of the important causes of folate deficiency include the following :

• Dietary : Inadequate intake of folate containing foods e.g. chronic alcoholism, psychiatric causes, elderly patients.
• Absorption : Impaired absorption in the gastrointestinal tracts e.g. celiac disease, tropical sprue, achlorhydria, anticonvulsant therapy, bacterial overgrowth in blind loops, strictures, adhesions, diverticula
• Metabolic : Impaired metabolism leading to inability to utilize folate in the body e.g. methotrexate and trimethoprim (folate antagonists) inhibit the enzyme dihydrofolate reductase involved in the formation of Tetrahydrofolate (active form of folate in the body)
• Hormonal : Hypothyroidism which leads to decreased hepatic levels of the enzyme dihydrofolate reductase
• Congenital : Deficiency of enzymes of folate metabolism
• Increased requirement : During infancy, pregnancy, lactation, malignancy, chronic hemolytic states (increased hematopoiesis), hemodialysis, peritoneal dialysis, inflammation.
• Increased loss : Vitamin B12 deficiency causes "folate trap" and inhibits the utilization of folate in the body, chronic alcoholism leads to increased excretion of folate into bile, excessive urinary excretion as in chronic dialysis

• Increased destruction : superoxides can inactivate folate

Pathogenesis

• The exact pathogenesis of [disease name] is not completely understood.

OR

• It is understood that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
• [Pathogen name] is usually transmitted via the [transmission route] route to the human host.
• Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
• [Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
• The progression to [disease name] usually involves the [molecular pathway].
• The pathophysiology of [disease/malignancy] depends on the histological subtype.

Genetics

[Disease name] is transmitted in [mode of genetic transmission] pattern.

OR

Genes involved in the pathogenesis of [disease name] include:

• [Gene1]
• [Gene2]
• [Gene3]

OR

The development of [disease name] is the result of multiple genetic mutations such as:

• [Mutation 1]
• [Mutation 2]
• [Mutation 3]

Associated Conditions

Conditions associated with [disease name] include:

• [Condition 1]
• [Condition 2]
• [Condition 3]

Gross Pathology

On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Microscopic Pathology

On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].