Etiopathogenisis of Oral Sub Mucous Fibrosis

 

Ms. Anju Mary Daniel¹, Dr. Eby Aluckal², Dr. Giju Baby George³, Dr. Mathews Baby⁴

¹Internship, Mar Baselios Dental College, Kothamangalam

²Assosiate Professor, Mar Baselios Dental College, Kothamangalam

³Professor, Mar Baselios Dental College, Kothamangalam

⁴Assistant Professor, Mar Baselios Dental College, Kothamangalam

 

ABSTRACT:

Oral sub mucous fibrosis is a premalignant condition mainly associated with the practice of chewing betel quid containing arecanut,a habit common among south Asian people. Commercially freeze dried products such as pan masala, gutka and  mava have high concentration of areca nut per chew and  appear to cause OSMF more rapidly than by self prepared conventional betel quid. It is characterized by inflammation, increased deposition of sub mucosal collagen mediated as a result of arecoline and formation of fibrotic bands in the oral and  Para oral tissues, which increasingly limit the mouth opening. Currently the role of genetic susceptibility and that of autoimmunity are receiving attention. The aim of this paper was to discuss the etiopathogenesis of oral sub mucous fibrosis.

 

 

 

INTRODUCTION:

Pindborg (1966) defined OSMF as “An insidious chronic disease affecting any part of the oral cavity and sometimes the pharynx, although occasionally proceeded by and/or associated with vesicle formation, it is always associated with juxta epithelial inflammatory reaction followed by fibro elastic change of the lamina propria, with epithelial atrophy leading to stiffness of the oral mucosa and causing trismus and inability to eat”¹,². The condition is well recognized for its malignant potential rate of 7.6% and is particularly associated with use of arecanut in various forms with significant duration and frequency of chewing habits³’. The features of which were described as a progressive narrowing of the mouth, blanching of the oral mucosa, pain and burning  sensation on taking food, hypo mobility of the soft palate and tongue, loss gustatory  sensation and occasional mild hearing impairment due to the blockage of the Eustachian tube.

 

There has been nearly no change in these symptoms till today. Management is  by restriction of  the habit, nutritional support, medicinal therapy  by the use of corticosteroids and proteolytic agents, lycopene therapy (safe antioxidant), pentoxifylline therapy, intralesional injections of steroid, placental extracts, hyaluronidase etc.

 

ETIOPATHOGENESIS:

Pathogenesis is believed to involve juxtaepithelial inflammatory reaction and fibrosis in the oral mucosa, probably due to an increased cross linking of collagen through up regulation of lysyl oxidase activity. Fibrosis or the building up of collagen, results from the effect of arecanut, which increases collagen production and decreases collagen degradation. Thus OSMF is now considered a collagen metabolic disorder. A multi factorial model for the pathogenesis of OSMF such as iron and nutritional deficiency, chronic candidiasis, tobacco, lime, betel quid, genetic abnormality, HSV, HPV, autoimmunity etc have been postulated and are known to have either have direct effect in causing OSMF or an indirect effect by mediating the immune system which is compromised in OSMF.

 

ROLE  OF  ARECANUT:

Currently, arecanut use is considered  to  be the most important  etiological factor for OSMF. The betel nut has psychotropic and antihelminthic property due to presence of areca alkaloids  The major arecanut alkaloid are arecoline, arecadine, arecolidine, guyacoline and guacine. Important flavinoid component in arecanut are tannins and  catechin. These alkaloids  undergo nitration and give rise to N-nitrosamine which might have cytotoxic effect on cells. Recent evidence suggest up regulation of the copper depended extra cellular enzyme lysyl oxidase by fibroblasts in oral sub mucous fibrosis is important, leading to excessive cross linking and accumulation of collagen. Arecanut alkaloids yield powerful carcinogenic nitrosamines¹. Thus chewing of arecanut may be an important factor in the etiology of OSMF¹¹.

 

ROLE OF TOBACCO AND CHILLIES:

Tobacco: oral sub mucous fibrosis shows an  increase in prevalence and has been shown to be precancerous and carries a high relative risk  for malignant conversion even after the control of tobacco use. Association of OSMF with carcinogens like tobacco was thought to have some relation with ROS. These are known irritants

and causative factors in oral malignancy. They may act as local irritants¹².

 

Chilies:

Chilies are thought to irritate the oral mucosa and cause an inflammatory reaction and along with continued use of chilies and other spices, continued irritation of the mucosa causes chronic inflammation, which leads  to fibrosis formation¹³. Capsaicin, which is vanillylamide of 8-methyl-6-nonenic acid, is the active ingredient of chilies, play an etiological role in oral sub mucous fibrosis .So chilies have indirect effect on the pathogenesis of OSMF as hypersensitivity to chilies is often explained as a common factor in the development of OSMF.

 

ROLE OF NUTRITIONAL DEFICIENCY:

A subclinical vitamin B complex deficiency has been  suspected in cases of  OSMF with vesiculations and ulcerations of oral cavity. The deficiency could be precipitated by the effect of defective nutrition due to impaired food intake in advanced cases and may be the effect , rather than the cause of the disease¹’¹. The reason for OSMF cases coming from  low socioeconomic group might be due to poor quality of food, low vitamins particularly in iron deficiency. Protein deficiency along with vitamin and iron deficiency leads to derangement in the inflammatory reparative response of the lamina propria with resultant defective healing and scarification which ultimately leads to OSMF.

 

ROLE OF HEAT SHOCK PROTEINS (HSP):

HSP47 MRNA was up regulated by arecoline in human BMFs. Thus the accumulation of collagen in oral mucosal connective tissue may be caused by a simultaneous effect on HSP47 by areca quid chewing¹.

ROLE OF BASIC FIBROBLASTIC GROWTH FACTOR (bFGF):

TGFβ is considered to be a potent stimulator of production and deposition of ECM¹. It is the main trigger for the increased collagen production and decreased matrix degradation pathways in OSMF¹. It has been shown that the expression of TGFb1 was significantly up regulated in the connective tissue portion of the disease compared to normal¹.

 

ROLE OF SALIVA:

Saliva of patients with OSMF contains a thrombin like substance, identified as fibrin production factor. In contrast fibrinolytic substance have been shown in normal saliva². Fibrin production factor in saliva interacts with plasma or fibrinogen in the sub mucous area of the oral cavity and produces dens fibrosis²¹.

 

ROLE OF HYPOXIA:

Hypoxia causes atrophy and ulceration of the epithelium by inducing apoptosis. In addition, the over expression of hypoxia-induced factor1 a is seen in OSMF, which indicates changes in all proliferation, maturation and metabolic adaptation increasing the possibility of malignant transformation²².

 

ROLE OF MAST CELLS:

When MCD increase there is an exponential increase in MVD proving that lesion is characterized by progressive fibrosis in early stages and there is a failure of  degradation or remodeling in the  advanced stages²³.

 

MOLECULAR PATHOGENESIS:

It was logical to hypothesize that the increased collagen synthesis or reduced collagen degradation as possible mechanism in the development of the disease². Collagen production pathway –there are three main events in this pathway that is activation of procollagen, elevation of procollagen, elevation of procollagen proteinase levels and up regulation of lysyl oxidase². Collagen degradation pathway consist of activation of tissue inhibitor of matrix metallo proteinase gene (TIMPs) and activation of plasminogen activator inhibitor gene. MMP-1 is the main human enzyme that degrades fibrillar collagen ,this suggests that collagen degradation caused by MMP-1 is down regulated in OSMF².

 

 

ROLE OF INFECTION:

HPV DNA, HSV DNA and EBV DNA were detected from patients with OSMF². A possible correlation exist  between RUT (Rapid urease test) reactivity and the  frequency of mucosal inflammation². C. dubiniensis was isolated from the oral cavities of both OSMF patients and healthy individuals².

 

GENETIC SUSCEPTIBILITY AND AUTO IMMUNITY:

A wide spectrum of chromosomal, genetic, and molecular alteration is associated with both pathogenesis and malignant transformation of OSMF, yet majority remains unclear³. The possibility of genetic susceptibility for this condition has been proved by CANNIFF et.al³¹. TH BS1, MMP2, ZO-1 and CK 18 were differentially expressed in the disease suggesting its importance in pathogenesis and also malignant transformation³². Further increase in arecoline concentration has inducedbothcellnecrosisandapoptosis³³. Circulating auto antibodies are also present in some cases of oral submucous fibrosis³. Suspicion of an autoimmune explanation for OSMF stems from certain similarities of this conditions with the other collagen disorders, namely scleroderma, which is persumed to have an autoimmune pathogenesis³’³.

 

Antinuclear(ANA), antismoothmuscle(SMA), antigastric parietalcell (GPCA), antithyroid microsomal (TMA) and antireticular antibodies were demonstrated in OSMF patients³. Areca nut chewing and/or smoking in OSMF and OSCC cases may play a role in the p53 over expression³. Alterations of the APC and wild type p53 tumour suppressor genes in OSMF may imply a risk for progression to oral cancer³. The enumeration of HARFC along with the estimation of serum levels of IgA, IgD and IgE indicates that OSMF can be an inter mediary stage in the malignant transformation of a normal cell.

 

ROLE OF MINERALS:

Significantly lower levels of hemoglobin and serum iron have been reported in OSMF by many authors¹’²’³’. In iron deficiency state, levels of cytochrome oxidase are low, consequently leading to epithelial atrophy. Serum zinc levels are decreased in patients with OSMF which can act as indicator for malignant transformation. Best predictors for the occurrence of lesions were age, serum iron, serum selenium in the decreasing order.

 

ROLE OF MICRONUCLEATED CELLS AND MICRONUCLEI:

In the patients with OSMF exfoliated cells were obtained by scraping from right and left buccal mucosa and were screened for micro nucleated cells and micronuclei. Frequency of micro nucleated cells and micronuclei in OSMF patients were high. The variation in the micro nucleated cells may be attributed to the factors like ingredients in the quid, frequency of quid per day and differing life style, gender, age and food habits.

 

ROLE OF OXIDATIVE STRESS:

OSMF, being a premalignant condition and associated with carcinogens like tobacco was thought to have some relation with ROS (Reactive oxygen species). Hence the present study was undertaken to assess blood levels of  lipid peroxidation products and antioxidant defence system in OSMF cases. Epidemiological studies have shown that the process of carcinogenesis occurs by generation of Reactiveoxygen species(ROS), which act by initiating lipid per oxidation(LPO).

 

CONCLUSION:

It is mandatory to have a thorough knowledge about the pathogenesis involved in the occurrence of OSMF as  the disease has no gold standard management since any form of treatment given causes morbidity to the patient. Hence various facts about the pathogenesis would ensure the oral physicians to formulate a standard treatment for the patients in need. Evidence suggests that OSMF is multifactorial, with certain effect on specific sub populations of fibroblasts, genetic predisposition and molecular mechanisms (cytokines and growth factors) which could render the oral mucosa more susceptible to chronic inflammatory changes on exposure to carcinogens.

 

REFERENCES:

1.       Pindborg J, Sirsat S, Oral sub mucous fibrosis. Oral surgery, oral medicine ,and oral pathology 1966;22(6):764.

2.       Rajendran R .oral sub mucous fibrosis :etiology, pathogenesis, and future research. Bulletin of the world health organization 1944;72(6):985-96.

3.       Phatak A. fibrin producing factor in oral sub mucous fibrosis Indian journal of otolaryngology and Head and neck surgery 1979;31(4):103-4.

4.       Rajendran R, Sugathan C, Ramani P, Ankathil R, Vijaya Kumar T. cell mediated and humoral immune responses in  oral sub mucous fibrosis. Cancer 1986;58(12):2628-31.

5.       Canniff J, Harvey W, Harris M. oral  sub fibrosis: its pathogenesis and management British dental journal  1986;160(12):429-34

6.       Sinor p, Gupta P, Murti P, Bhonsle R, Dafffary D, Mehta F, Pndvorg J. a case   control study of oral sub mucous  fibrosis  with special  reference to the  etiologic role of arecanut . Journalof oral pathology and medicine 1990;    19(12):94-8.

7.       Auluck A, Rosin M. P, Zhang L, Sumanth  K.N. oral  sub  mucous     fibrosis , a clinically benign and potentially malignant disease:report of 3 cases and review of literature

8.       Pillai R, Balram P, Reddiar K. S. pathogenesis of oral sub mucous fibrosis: relationship to risk factors associted with oral cancer 1992;69:2011-20.

9.       K Kiran kumar, T.R Saraswathy, K Ranganadhan, M umadevi, Joshna elizabath.oral sub mucous fibrosis:a clinic o-histopathological study in chennai. IJDR 2007;18:106-111.

10.     IARC Aconymous tobacco habits other than smoking :betel quid and arecanut chewing and some related nitrosamines. IARC Monogr Eval carcinog risk  chem hum 1985;37:141-200.

11.     MaRH, Tsaicc, Shieh TY. increased lysyl oxidise activity in fibroblast cultured from oral sub mucous fibrosis associated with betel nut chewing in Tainwan J oral pathol med 1995;24:407-12.

12.     Hoffmann D, Rivenson A, Prokopczykd, Brunnemannk.D, Carmella SG, Hoffmanni. Advaces in tobacco carcinogenesis I. smokeless tobacco and betel quid in : Gupta PC, Hamlerje, Murti PR, eds. control of tobacco related cancers and other diseases. Bombay. Oxford University press 1992.pp.193-204.

13.     Gupta PC et al. incidence rates of oral cancer and natural history of oral precancerous lesions in a 10 year follow up study of Indian villages .community dent. Oral epidemiol ,1980,8:287-331.

14.     Sinor PN, Gupta PC , Murti PR, et al .a case control  study of oral sub mucous fibrosis with special reference to the Etiologic role of arecanut. J oral pathol med 1990;19:94-8.

15.     Ahmad MS. Epidemiological  and etiological study of oral submucous fibrosis among Gutkha chewers of Patna, Bihar, India. J Indian Soc pedod prev Dent –June 2006.84-89.

16.     M.K Gupta oral submucous fibrosis-current concepts in Etiopathogenesis: people’s journal of scientific research:vol 1-July 08:

17.     Rajendran R. Oral submucousfibrosis: Etiology. pathogenesis and future research. Bull WHO 1994;72:985-96

18.     Tilakaratone W. M, Klinikowski MF, Saku T, Peters TJ, Warnakulasuriya S. oral sub mucous fibrosis: Review on etiology and pathogenesis. Oral Oncol 2006;42(6):561-8.

19.     Dyavanagoudar SN. Oral sub mucous fibrosis: review on etiopathogenesis. J cancer sci Ther 2009;1:72-7.

20.     Rasika Pawiththra Illeperuma, Mi Heon Ryu, Kiyeol Kim W. M. Tilakaratne, Jin Kim (2010) relationship of fibrosis and the expression of TGFb1,MMP1 and TIMP-1 with epithelial dysplasia in oral sub mucous fibrosis. Oral Med Pathol 15:25-32

21.     Yadav S, Verma A, Sachdeva A, Virdi MS. Etiopathogenesis and management of oral sub mucous fibrosis. The internet journal of bioengineering 2011;5(1):do I;10.5580/217.

22.     Khan I, Kumar N, Pant I, Narra S, Kondaiah P(2012)activation of TGF pathway by areca nut constituents:a possible cause of oral sub mucous fibrosis.plos onet:e51806

23.     Mountasian Karwan A, Jenel Veronika, Sapienza Karen, Marsh Daniel, Weinreb paul H.et al(2011)Betel derived alkaloid upregulates keratinocyte alpha beta 6 integrin expression and promotes oral sub mucous fibrosis journal of pathology 223:366-377.

24.     Rasika Pawiththra Illeperuma, Mi Heon Ryu, Kiyeol Kim W. M. Tilakaratne, Jin Kim (2010) relationship of fibrosis and the expression of TGFb1,MMP1 and TIMP-1 with epithelial dysplasia in oral sub mucous fibrosis. Oral Med Pathol 15:25-32.

25.     Phatak AG. Fibrin producing factor in oral sub mucous fibrosis. Indian J orolaryngol 1979;31:103-4.

26.     Phatak AG. Oral sub mucous fibrosis-a chronic disseminated intravascular coagulation syndrome with local coagulopathy. Gut 1993;33:713.

27.     Tilakarne WM, Iqbal Z, Tech MT, Ariyawardana A, Pitiyage G, Cruchley A et al. regulation of HIF1a in malignant transformation of oral submucous fibrosis. Joralpathol med2008;37: 375-7  

28.     Sabarinath B, Sriram G, Saraswathi TR, Sivapathasundharan B. Immunohistochemical evaluation of mast cells and vascular endothelial proliferation in oral sub mucous fibrosis. Indian J Dent Res  2011;22:116-21.

29.     Jalouli J, Ibrahim SO, Mehrotra R, Jalouli M. M, Sapkota D,Larssan P.A et al. prevalence of viral infections in oral sub mucous fibrosis and oral cancer from India. Acta Otolaryngol 2010;130(11):1306-11

30.     Rajendran R, Rajev R, Anil S, Alasquah M, Rabi AG. Helicobacter pylori coinfection is a confounder  ,modulating mucosal inflammation in OSMF, Indian J Dent Res 2009;2012:206-11.

31.     Ariyawardana A, Panagoda GJ, Fernado HN, EllepolaAN, Tilakaratne WM, Samaranayake LP et al.oral sub mucous fibrosis and oral yeast carriage-a case controle study in srilankan patients mycoses.2007;50(2):116-20.

32.     Mithani SK, Mydiarz WK, Grumbine FL, Smith IM, Califano JA(2007) molecular genetics of premalignant oral lesions.oral dis 13:126-133.

33.     Canniff JP, Harvey W, Harris M, Oral sub mucous fibrosis :its pathogenesis and management.Br Dent J 1986:160:429-34.

34.     HUY, Jian X, Peng J, Jiang X, LiN, et al(2008) gene expression profiling of oral sub mucous fibrosis using aligo nocleotide microarray. Oncol Rep 20:287-294.

35.     Lee PH, Chang MC, Chang WH, Wang TM, Wang YJ et al (2006)prolonged exposure to arecoline arrested human KB epithelial cell growth, regulatory mechanisms of cell cycle and apoptosis. Toxicology 220:81-89.

36.     Cannif JP, Harvey W, Harris Moral submucous fibrosis: reprint requests to: pathogenesis and management.Br Dent J 1986;160:429-34.

37.     Kallenbberg CGM, Van Der Voort-Beelen JM, D’amaroj THE TH.scleroderma:increased frequency of B8/DR3 in scleroderma and association of the haplotype with impaired cellular immune response. Clin Exp Immunol 1981:43:475-85.

38.     Whiteside TL, Medsger TA, JR, Rodnan GP,Hla DR antigens in progressive systemic sclerosis.J Rheumatol 1983:10:163-7.

39.     Chiang CP, Hsieh RP, Chen THH, Chang YF, Liu BY, Wang JT, et al. High incidence of autoantibodies in Taiwanese patients with oral sub mucous fibrosis. J oral pathol med 2002;31:402-9.

40.     Sulthana N, Pallagatti S, Mohammed Al.p53 expressions in oral sub mucous fibrosis and oral cancer. International journal of oral and maxillofacial pathology;2011:2(1):9-14.

41.     Liao PH, Lee TL, Yang LC, Yang SH, Chen SL, Chen MY, Adenomatous poliposis coli gene mutation and decreased wild type p53 protein expression in oral sub mucous fibrosis:a peliminary investigation. Oral Surg Oral Med Oral  Pathol oral Radiol Endol.2001;92(2):202-7.

42.     Rajendran R, Sughathan CK, Remani P, Aukathil R, Vijayakumar T cell mediated and humoral immune responses in OSMF. cancer 1986;58(12):2628-31.

43.     VargheseI, Sugathan CK, Balasubramoniyam G, Vijayakumar T .serum  copper and zinc levels in premalignant and malignant lesions of the oral cavity. Oncol 1987:44:224-7.

44.     Sonali K, Freny K, Immunological and biochemical markers in oral precancer and cancer ;A study .JIAOMR 2005;17(4):161

45.     Khanna Sunali S, Karjodkar Freny R. Circulating immune complexes  and trace elements (copper, iron, and selenium) as markers in oral precancer and cancer. A randomized controlled clinical trial. Head face med 2006;2:33.

46.     Anila K, Kaveri H, Naikmasur VG. Comparative study of oral micronucleated cell frequency in oral sub mucous fibrosis patients and healthy individuals. J Chin Exp Dent 2011;3(3);e 201-6.

47.     Holland N, Bolognesi C, Kirsch-volders M. Bonassi S, Knasmueller S, et al. The micronucleus assay in human buccal cells as a tool for biomonitoring DNA damage :the Human project perspective on current status and knowledge gaps. Mutat Res 2008; 659:93-108.

48.     Sun, Yi. (1990)Free radicals antioxidant enzymes and carcinogenesis. Free radical Biol .Med.8,583-599.

49.     Freeman, B.A, and Crapo ,J.D(1982) free radicals and tissue injury .Lab.47,412-425.

 

 

 

 

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