|Year : 2013 | Volume
| Issue : 3 | Page : 145-152
Folic acid: A positive influence on periodontal tissues during health and disease
Joann Pauline George1, R Shobha2, Flemingson J Lazarus3
1 Department of Periodontics, Krishnadevaraya College of Dental Sciences, Krishnadevarayanagar, Hunsmaranahalli, India
2 Department of Periodontics, M R Ambedkar Dental College, Bangalore, India
3 Department of Periodontics, Best Dental College, Madurai, India
|Date of Web Publication||25-Oct-2013|
Joann Pauline George
Department of Periodontics, Krishnadevaraya College of Dental Sciences, Krishnadevarayanagar, Hunsmaranahalli, Bangalore 562 157
Source of Support: None, Conflict of Interest: None
Periodontal disease is a multifactorial disease, the origin of which remains obscure. However, the manifestation and progression of periodontitis is influenced by a wide variety of determinants including social and behavioral factors, systemic factors, environmental and genetic factors. Periodontal tissue integrity is dependent on the adequate intake of proteins, carbohydrates, fats, vitamins, and mineral salts. Chronic deficiencies in the availability of one or more of these nutrients are expected to produce pathological alterations in the expression and progression of periodontal disease. Folic acid, also known as vitamin B 9 or folacin, is one such vitamin that is essential for numerous bodily functions ranging from nucleotide biosynthesis to the remethylation of homocysteine. Folic acid deficiency causes absence of keratinization of gingival surface, decreased resistance to infection, necrosis of gingiva, periodontal ligament, and alveolar bone destruction in animals and humans. This may be accompanied by ulcerative glossitis and cheilitis. Repair and maintenance of periodontal tissues generates a high turnover rate of squamous epithelium and without folic acid, epithelial cells do not divide properly. Folic acid deficiency is the most common nutrient deficiency in the world. Organic nitrites, nitrous oxide, cyanates, and isocyanates found in cigarette smoke have been shown to interact with folic acid, transforming them into biologically inactive compounds and thereby leading to lower folic acid levels in serum, red blood cells, and respiratory tract. Folic acid supplementation as an adjunct in the management of periodontal disease in smokers will prove to have beneficial effect on the periodontal tissues during repair and turnover.
Keywords: End-organ deficiency, folic acid deficiency, folic acid supplementation, non-surgical periodontal therapy, periodontal disease, smoking
|How to cite this article:|
George JP, Shobha R, Lazarus FJ. Folic acid: A positive influence on periodontal tissues during health and disease
. Int J Health Allied Sci 2013;2:145-52
|How to cite this URL:|
George JP, Shobha R, Lazarus FJ. Folic acid: A positive influence on periodontal tissues during health and disease
. Int J Health Allied Sci [serial online] 2013 [cited 2020 Oct 25];2:145-52. Available from: https://www.ijhas.in/text.asp?2013/2/3/145/120582
| Introduction|| |
Periodontal health relies on a delicate balance between the host, environment, bacteria, and other microorganisms. Periodontal disease is the result of complex inter-relationships between infectious agents and host factors. Environmental, acquired, and genetic risk factors modify the expression of disease and may, therefore, affect the onset, progression of the disease, and the response to treatment.
Tobacco smoking is one of the age-old habits and is proven to be linked with cancer. It also plays a role as an environmental factor and is associated with an increased prevalence and severity of periodontal disease and is also known to negatively influence the levels of nutrition too. Nutrition is one of the modifiable factors that impact the host's immune response and the integrity of the hard and soft tissues of the oral cavity. ,
Periodontal health depends strongly upon an adequate source of essential nutrients being available to the host.  The epithelium of the dentogingival junction and the underlying connective tissues are among the most dynamic tissues in the body. The maintenance of the healthy periodontium is dependent upon an adequate supply of proteins, carbohydrates, fats, vitamins, and mineral salts. Chronic deficiency in any of these nutrients may be expected to produce pathological alterations in the periodontal tissues. 
Periodontal disease is the result of an increase in the virulence factors of the infecting organisms and the decreased resistance of the host.  Nutritional deficiencies also modify periodontal destruction, but their exact mechanisms have not been precisely defined. Nutritional deficiencies may affect any of the basic periodontal defense factors such as the integrity of the dentogingival barrier and the turnover of its constituent cells. 
The B-complex vitamins, such as niacin, thiamin, riboflavin, folic acid, and B12, are co-factors in energy metabolism and are needed in DNA and RNA synthesis. This makes them indispensable for tissue maintenance and production of new cells during development and healing. The most common symptom of vitamin B deficiencies is loss of the integrity of the oral mucosa. The oral manifestations of the loss of integrity include stomatitis, angular cheilitis, and glossitis.
Vitamin C prevents oxidative cell damage and aids in maintaining the integrity of the oral mucosa. Gingival inflammation appears to be one of the most sensitive indicators of vitamin C deficiency, which may be related to the vitamin's role in maintaining the microvasculature of the sulcus.
Other nutrients such as proteins, vitamin A, and zinc are important in DNA and RNA replication, transcription of RNA, and the translation of proteins and also are necessary for new cell growth.
Nutrients function together and nutrient deficiencies rarely occur in isolation, hence it is important to have adequate supplies of all nutrients to ensure adequate growth and maintenance of the oral tissues.
Purpose of the review
Folic acid deficiency is the most common nutrient deficiency in the world. Organic nitrites, nitrous oxide, cyanates, and isocyanates found in cigarette smoke have been shown to interact with folic acid, transforming them into biologically inactive compounds and thereby leading to lower folic acid levels in serum, red blood cells, and respiratory tract. Folic acid supplementation as an adjunct in the management of periodontal disease in smokers will prove to have beneficial effect on the periodontal tissues during repair and turnover. Hence, a review on the role of gingival health and the benefits of folic acid supplementation in deficiency states has been discussed.
Vitamins are essential and biologically active constituents of a diet, which cannot be replaced by other dietary components.  The absence or scarcity of certain vitamins has been implicated as being etiological factor in the pathogenesis of periodontal diseases.  The vitamin B complex includes thiamin, riboflavin, niacin, pyridoxine, biotin, folic acid, and cobalamin. Oral changes that are common to B-complex deficiencies are gingivitis, glossodynia, angular cheilitis, and inflammation of the entire oral mucosa.
Folic acid deficiency results in macrocytic anemia with megaloblastic erythropoiesis, accompanied by oral changes, gastrointestinal lesions, diarrhea, and intestinal mal-absorption.  Folic acid-deficient animals demonstrate necrosis of the gingiva, periodontal ligament, and alveolar bone. The absence of inflammation is the result of deficiency-induced granulocytopenia. In humans with sprue and folic acid deficiency, generalized stomatitis occurs, which may be accompanied by ulcerative glossitis and cheilitis. 
Oral disturbances that have been attributed to thiamin deficiency include hypersensitivity of the oral mucosa; minute vesicles (simulating herpes) on the buccal mucosa, under the tongue, or on the palate; and erosion of the oral mucosa. The symptoms of riboflavin deficiency include glossitis, angular cheilitis, seborrheic dermatitis, and a superficial vascularizing keratitis. Niacin deficiency results in glossitis and stomatitis. The gingiva may be involved in aniacinosis with or without tongue changes. The most common finding is necrotizing ulcerative gingivitis (NUG), usually in areas of local irritation.
Vitamin C deficiency causes scurvy, characterized by hemorrhagic diathesis, and delayed wound healing.  Vitamin A deficiency results in degenerative changes in epithelial tissues, resulting in a keratinizing metaplasia. The effect of vitamin D deficiency or imbalance on the periodontal tissues results in osteoporosis of alveolar bone, osteoid that forms at a normal rate but remains uncalcified, failure of osteoid to resorb, which leads to its excessive accumulation; reduction in the width of the periodontal ligament space; a normal rate of cementum formation, but defective calcification and some cementum resorption; and distortion of the growth pattern of alveolar bone. No relationship has been demonstrated between deficiencies in vitamin E and oral disease, but systemic vitamin E appears to accelerate gingival wound-healing in the rats.
| Folic acid|| |
Folic acid (also known as vitamin B 9 or folacin) and folate (the naturally occurring form), pteroyl-L-glutamic acid, and pteroyl-L-glutamate, are forms of the water-soluble vitamin B 9 .  Vitamin B 9 (folic acid and folate inclusive) is essential for nucleotide biosynthesis to the remethylation of homocysteine. , Homocysteinemia occurs due to an abnormally high plasma level of homo-cysteine, the de-methylated derivative of the amino acid methionine, which is an independent risk factor for cardiovascular disease. , Elevated plasma homocysteine has been connected to increased risk of neural tube defects and other birth defects, as well as to schizophrenia, Alzheimer's disease, cognitive decline, osteoporosis, rheumatoid arthritis, kidney failure, and cancer. ,
The activated coenzyme form of folic acid (5-methyltetrahydrofolate) is needed for optimal homocysteine metabolism, since it acts as a methyl donor, providing a methyl group to vitamin B12. The methylated form of vitamin B12 (methylcobalamin) subsequently transfers this methyl group to homocysteine. The result is a recycling of homocysteine to methionine, resulting in reduction in elevated plasma homocysteine.
Folic acid is important during periods of rapid cell division and growth. Both children and adults require folic acid to produce healthy red blood cells and prevent anemia. Folate and folic acid derive their names from the Latin word folium (which means "leaf.")
Relationship of folic acid and pregnancy
During pregnancy, there are increased levels of estrogen and progesterone that affects not only the organs of reproduction but also modifies the reactions of several basic tissues.  Hugoson in 1971 has demonstrated a significant correlation between the level of sex hormones during pregnancy and the severity of gingival inflammation, which was not accompanied by an increase in bacterial plaque. Whitehead in 1973 has suggested that there was a strong interrelationship exists between sex hormones and folate coenzymes and the rate of folate metabolism may increase in pregnancy. End-organs may be affected more severely than other areas, and folic acid too showed a similar end-organ deficiency without demonstrable evidence of systemic folate deficiency.
Low dietary intake of folic acid increases the risk for delivery of a child with a neural tube defect (NTD). Periconceptional folic acid supplementation significantly reduces the occurrence of NTD.
Supplemental folic acid intake during pregnancy results in increased infant birth weight and improved Apgar scores. 
Inflammatory bowel disease
Patients with inflammatory bowel disease (IBD) often have folate deficiencies, caused in part by the drug sulfasalazine, prescribed for IBD but also known to inhibit folate absorption. Evidence suggests folic acid supplementation might lower the risk, in a dose-dependent fashion, of colonic neoplasia in patients with ulcerative colitis.
The role of folic acid in gingival health and disease [Table 1]
|Table 1: Representing the various facets of folic acid and it's influence on gingival health and disease |
Click here to view
Folic acid is utilized by virtually all mammalian cells as a coenzyme for amino acid conversions and synthesis of pyrimidine and purine needed for deoxyribonucleic acid (DNA) synthesis.  It is required for cellular division and new cell production. Folate coenzymes function in the single-carbon-transfer reactions involved in amino acid conversions, methyl-group biogenesis, and nucleoprotein formation. At the cellular level, the major defect in folic acid deficiency is an impaired production of deoxyribonucleic acid (DNA) expressed as inefficient mitosis, increase in cellular stroma, and asynchronism between protein synthesis and cell division.  Interference with DNA synthesis disrupts the production of messenger ribonucleic acid (RNA) and prevents the process of cell maturation from reaching completion, a factor that would account for the mucosal changes found in the folic acid deficiency conditions.  Histologically, the most prominent folic acid deficiency-related changes were an interference with the maturation of the epithelial cells, impairment of keratinization, and an increased susceptibility to ulceration and secondary infection (Dreizen, 1970). Repair and maintenance of the periodontium generates a high turnover rate of squamous epithelium, thus folic acid is essential for the proper maturation of the rapidly proliferating cells (Staats 1965, Gardner 1956). It is thus conceivable that gingival epithelium would also be affected in folic acid deficiency.
Dreizen in 1970 noted that there were significant histopathological changes in folic acid deficiency marmosets. Histologically, there were thickening of the delimiting membrane, finely dispersed and lightly stained cytoplasm, lacy appearance of nuclei with fragmentation and clumping of chromatin, reduction in the number and size of keratohyaline granules, diminished or completely abolished ability to form keratin.
Each of the folic acid-deprived marmosets had moderate to severe generalized gingivitis and periodontitis. Some also showed infrabony pocket formation. In these marmosets, the intestinal villi were thickened, shortened, widened, branched edematous, occasionally coalescent, and always heavily infiltrated with acute and chronic inflammatory cells. By comparison, all the marmosets given the daily dietary supplement of folic acid had an intact mucosa. Marmosets deprived of dietary folic acid had an exceedingly high incidence of oral infections.
Keratinization of the cornified mucosa, which is indicative of cytologic maturity, has been shown to be influenced by estrogens. A lack of folic acid interferes with estrogen induced tissue growth and maturation. The susceptibility to oral infection has been attributed to the ensuing granulocytopenia and anemia that lower host resistance.
Folic acid deficiency
As folic acid deficiency has been associated with abnormalities in rapidly proliferating epithelial cells,  it is conceivable that the junctional epithelium would also be affected. The maturation of junctional epithelium, which has a rapid turnover rate, is a prime importance in the prevention and control of periodontal disease. Folic acid deficiency is associated with severe gingival inflammation (Vogel).  Whitehead in 1973 also introduced the concept of end-organ deficiency to indicate a relative deficiency of folate occurring in certain tissues despite normal plasma folate levels. Vogel in 1976 applied the term "end-organ deficiency" in connection with inflammatory changes of the gingivae, which were responsive to both topical and systemic folate administration. An end-organ deficiency of folic acid can exist even though blood levels are normal. Folic acid deficiency in gingivitis patients as compared to patients supplemented with folic acid have shown to increase bleeding on probing, increase gingival exudate, and both clinical and histological evidence of severe gingival inflammation.
Folic acid deficiency leads to absence of keratinization of gingival surface.  Decreased resistance to infection is also noted among folic acid-deficient individuals. Folic acid-deficient animals also demonstrate necrosis of the gingiva, periodontal ligament, and alveolar bone without inflammation. The absence of inflammation is the result of deficiency-induced granulocytopenia.
Smoking and folic acid
Cigarette smoking is one of the factors that negatively affect the levels of vitamin B12 and folic acid.  Active cigarette smokers have lower folic acid levels in their serum, red blood cells, and respiratory tract.  Cigarette smoking is associated with increased plasma homocysteine concentrations and a pro- inflammatory and prothrombotic activity (Heimburger, 1992). Homocysteine is a sensitive marker of vitamin B 12 and folic acid deficiencies. An inverse relationship between low folate levels and high homocysteine levels in smokers is associated with increased risk of cardiovascular disease.
Cigarette smoke is known to contain nitric oxide (NO), superoxide, and other reactive oxygen species; some of the adverse effects of smoking may result from oxidative damage to endothelial cells, which results in nitric oxide shortage.  During inflammatory reactions, where large amounts of nitric oxide and superoxide are formed, the combination of both leads to the formation of reactive nitrogen species, such as the peroxynitrite anion, a toxic product of NO when combining with superoxide. The tissue injury induced by per-oxynitrite may lead to an excessive local amplification of the immune response, resulting in migration of inflammatory cells. 5-methyl tetrahydrofolic acid, the active form of folic acid, has shown to reduce superoxide generation, thus providing antioxidant potential. On the other hand, free radicals and oxidants, which cause DNA and membrane damage, are present in high levels in tobacco smoke and may also play a role in decreasing the folic acid levels.
Organic nitrites, nitrous oxide, cyanates, and isocyanates found in cigarette smoke have been shown to interact with folic acid and vitamin B12 co-enzymes, transforming them into biologically inactive compounds.
Smoking, folic acid, and periodontal disease
Besides the adverse effects of smoking on immunology and the host-bacterial interactions, this may account for its deleterious effects on periodontal health;  smoking also negatively affects vitamin B12 and folic acid mechanisms.  The deficiency of these vitamins may be detrimental for the growth and development of the periodontium and
also in the expression and progression of periodontal diseases.
Folic acid supplementation and its influence in gingival and periodontal health and disease
Folic acid supplementation can be attempted both systemically and topically.  It is available in various forms like mouthwash, tablets, capsules, and injections. Dietary supplementation of 2 mg systemic folic acid showed an increase in the resistance of gingiva to local irritants and thus led to a reduction in inflammation over a 30-day period (Vogel, 1976).  In another instance, the use of 5 ml folate mouthwash rinse twice-daily for 4 weeks for 1 min on established gingivitis in non-pregnant adults showed improved gingival health (Angela R C Pack, 1984).  Systemic folic acid (5 mg/day) in combination with oral hygiene measures in prevention of phenytoin-induced gingival overgrowth showed that after one year, gingival overgrowth was delayed in children (Prasad V N, 2004).  Evidence such as these present in the literature indicate that in a folic acid deficiency-prone situation, the management and maintenance of periodontal health and disease will be positively influenced by folic acid supplementation.
Gingival hyperplasia is a common adverse effect of therapy with phenytoin. Poor periodontal hygiene is an important risk factor for severity of phenytoin-induced gingival overgrowth (PIGO), which is a time-dependent process. There is complex interplay of altered fibroblast biology, connective tissue turnover, inflammatory processes, and growth factors on a background of genetic susceptibility to produce increase in various components of interstitial matrix in PIGO tissue. There is conclusive evidence that folic acid supplementation significantly decreases the incidence of PIGO. Oral folic acid supplementation, 0.5 mg/day, is associated with prevention of gingival overgrowth in children taking phenytoin monotherapy. 
Folic acid supplementation in smokers
It has been seen that among periodontal disease patients, smokers display significantly reducing levels of folic acid over a period of 6 months after non-surgical periodontal therapy. , Smoking exerted a negative influence on the clinical outcome following non-surgical periodontal therapy. With the proven role of folic acid in maintaining the integrity of periodontal tissues and also keeping in mind the rampant alterations it induces to the sensitive physio-chemical balance at the epithelial- connective tissue interface, folic acid supplementation to smokers will be definitely a beneficial therapeutic approach. Any periodontal treatment in smokers should include effects to make the patients quit smoking and also include diets rich in folic acid, which may prove to be beneficial in the post-therapeutic healing and maintenance. Dietary supplementation of folic acid can show beneficial effects on the periodontal tissues of smokers with chronic periodontal disease following non-surgical periodontal intervention. ,
Epidemiological studies gathering data on association between folic acid, smoking, and periodontal diseases will help to identify the three pronged association. Randomized clinical trials aimed at folic acid supplementation as an adjunct to non-surgical periodontal intervention in smokers with chronic periodontitis can be undertaken to justify the beneficial effect of folic acid in smoker with periodontal disease.
| Conclusion|| |
Folic acid is essential for the maintenance of an intact oral mucosa. Folic acid deficiency impairs the maturational sequence of the oral mucosal epithelium and depresses the hematologic elements that help prevent and combat infections in this region.
Low levels of serum folate were independently associated with periodontal disease in older adults; hence, it is quite possible to presume that smoking-induced folic acid deficiency can negatively influence periodontal disease expression and progression. Thus, folic acid supplementation as an adjunct in the management of periodontal disease in smokers will prove to be beneficial. Oral mucosal integrity can be protected by the inclusion of daily supplements of folic acid.
| References|| |
|1.||Nunn ME. Understanding the etiology of periodontitis: An overview of periodontal risk factors. Periodontol 2000 2003;32:11-23. |
|2.||Seymour RA, Heasman PA. Drugs, diseases and the periodontium. New York; Oxford University Press; 1992. |
|3.||Apatzidou DA, Riggio MP, Kinane DF. Impact of smoking on the clinical, microbiological and immunological parameters of adult patients with periodontitis. J Clin Periodontol 2005;32:973-83. |
|4.||Grant DA. Periodontics. 6 th ed. St Louis (Washington): Mosby Company; 1988. |
|5.||Bender DA. Nutritional biochemistry of the vitamins. Cambridge, U.K: Cambridge University Press; 2003. |
|6.||Folic acid monograph. Altern Med Rev 2005;10:222-9. |
|7.||Boyd LD, Lampi KJ. Importance of Nutrition for Optimum Health of the Periodontium. J Contemp Dent Pract 2001;2:36-45. |
|8.||Volker JF. The relation of nutrition to periodontal disease. J Dent Res 1962;41:264-78. |
|9.||Piyathilake CJ, Macaluso M, Hine RJ, Richards EW, Krumdieck CL. Local and systemic effects of cigarette smoking on folate and vitamin B-12, Am J Clin Nutr 1994;60:559-66. |
|10.||Abu Khaled M, Watkins CL, Krumdieck CL. Inactivation of B12 and folate coenzymes by butyl nitrite as observed by NMR: Implications on one-carbon transfer mechanism. Biochem Biophys Res Commun 1986;135:201-7. |
|11.||Erdemir EO, Bergstrom J. Relationship between smoking and folic acid, vitamin B 12 and some hematological variables in patients with chronic periodontal disease. J Clin Periodontol 2006;33:878-84. |
|12.||Erdemir EO, Bergstrom J. Effect of smoking on folic acid and vitamin B 12 after non surgical periodontal intervention. J Clin Periodontol 2007;34:1074-81. |
|13.||Wang G, Dai J, Mao J, Zeng X, Yang X, Wang X. Folic acid reverses hyper-responsiveness of LPS-induced chemokine secretion from monocytes in patients with hyperhomocysteinemia, Atherosclerosis 2005;179:395-402. |
|14.||Pulikkunnel ST, Thomas SV. Neural tube defects, pathogenesis and folate metabolism. J Assoc Physicians India 2000;53:127-35. |
|15.||Vogel RI, Fink RA, Frank O, Baker H. The effect of topical application of folic acid on gingival health. J Oral Med 1978;33:20-2. |
|16.||Vogel RI, Fink RA, Schneider LC, Frank O, Baker H. The effect of folic acid on gingival health. J Periodontol 1976;47:667-8. |
|17.||Newman MG, Takei HH, Klokkevold PR, Carranza FA, editors. Carranza's Clinical periodontology. 10 th ed. St Louis: Elsevier; 2006. |
|18.||Enwonwu CO, Sanders C. Nutrition: Impact on oral and systemic health. Compend Contin Educ Dent 2001;22:12-8. |
|19.||Bergstrom J. Cigarette smoking as risk factor in chronic periodontal disease. Community Dent Oral Epidemiol 1989;17:245-7. |
|20.||Pack AR. Folate mouthwash: Effects on established gingivitis in periodontal patients. J Clin Periodontol 1984;11:19-628. |
|21.||Prasad VN, Chawla HS, Goyal A, Gauba K, Singh P. Folic Acid and Phenytoin Induced Gingival Overgrowth-Is There A Preventive Effect. J Indian Soc Pedo Prev Dent 2004;22:82-91. |
|22.||Arya R, Gulati S, Kabra M, Sahu JK, Kalra V. Folic acid supplementation prevents phenytoin-induced gingival overgrowth in children. Neurology 2011;76:1338-43. |