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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 30  |  Issue : 3  |  Page : 265-270

Betel-nut-induced oral lichenoid lesion in oral submucous fibrosis and its relation with liver enzymes and hepatitis C virus-ribonucleic acid


1 VYWS Dental College and Hospital, Amravati, Maharashta, India
2 Department of Oral Diagnosis Medicine and Radiology, Sharad Pawar Dental College, Sawangi (Meghe), Wardha, Maharashta, India

Date of Submission30-Mar-2018
Date of Acceptance10-Jul-2018
Date of Web Publication18-Oct-2018

Correspondence Address:
Dr. Shashwati H Choube
VYWS Dental College and Hospital, Amravati, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jiaomr.jiaomr_48_18

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   Abstract 


Introduction: Reticular, annular, and pigmented lichenoid lesionsare associated with oral submucous fibrosis (OSMF). Both, betel-nut alkaloid and aflatoxin are responsible for hepatic damage. Occurrence of hepatic disorder with hepatitis C infection is associated with lichen planus. Considering the co-relation of oral lichen planus (OLP) with hepatitis C infection and similar lichen-planus-like lesion in OSMF probe to investigate the co-relation of liver enzymes and hepatitis C virus and OSMF associated with oral lichen-planus-like lesion. Methods: A cross-sectional case–control study was conducted on total 60 patients. Out of 60 patients, 20 were with lichen-planus-like lesions with OSMF, 20 with OSMF, and 20 healthy individuals. The sera of the patients and controls were tested for HCV (RNA) using Mini Vidas and liver function tests (bilirubin, transaminases, and alkaline phosphatase). Results: Among the total 60 patients, OLP-like lesions with OSMF patients had higher serum bilirubin, transaminases, and alkaline phosphatase level as compared with control patients. Conclusions: Increased titer of HCV-RNA with increased liver enzymes was found in OSMF with betel-nut-induced lichenoid lesions. This demonstrates the dual action of betel-nut alkaloids with plausible role of aflatoxin in liver damage in OSMF.

Keywords: Alkaline phosphatase, hepatitis C virus-ribonucleic acid, oral submucous fibrosis, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase


How to cite this article:
Choube SH, Bhowate RR. Betel-nut-induced oral lichenoid lesion in oral submucous fibrosis and its relation with liver enzymes and hepatitis C virus-ribonucleic acid. J Indian Acad Oral Med Radiol 2018;30:265-70

How to cite this URL:
Choube SH, Bhowate RR. Betel-nut-induced oral lichenoid lesion in oral submucous fibrosis and its relation with liver enzymes and hepatitis C virus-ribonucleic acid. J Indian Acad Oral Med Radiol [serial online] 2018 [cited 2019 Jun 19];30:265-70. Available from: http://www.jiaomr.in/text.asp?2018/30/3/265/243657




   Introduction Top


Betel-nut is a major etiological factor for oral submucous fibrosis (OSMF). Psychoactive properties of areca-nut alkaloid are responsible for addiction of habit.[1] Areca nut is the fourth most commonly used psychoactive substance in the world, after caffeine, alcohol, and nicotine.[1] Betel-nut-specific nitrosamines have been identified, which are responsible for the premalignant and malignant oral mucosal lesions/conditions.[2]

Hepatitis C virus infection is supposed to be potential factor for increasing oral lichen planus (OLP) susceptibility and has been reported as an extra-hepatic manifestation of HCV infection.[3] Aflatoxin B1 is the most abundant and toxic member of family and been classified by the World Health Organization as “group A” carcinogen because of its proven contribution to the pathogenesis of hepatocellular carcinoma and used as marker of HCV infection in asymptomatic patients.[4]

Indian study revealed that 37.5% samples were infested with Aspergillus flavus.[5] Grace Hui Min Wu, Boucher BJ, and Chu YH reported 4.25-fold risk of hepatic damage in individuals' habitual of areca-nut.[6] Both synergistic and additive effects of areca-nut alkaloid and aflatoxin are responsible for immunosuppression and result in hepatic damage.[4],[5],[6]

OLP-like, oral mucosal lesions are seen in betel-nut habitual presented with annular, reticular, or plaque-type lesion in the background of melanosis. In both the lesions, clinical and histopathological features are similar and could not be differentiated except betel--nut habit.[7] Association of hepatitis C virus infection in OLP patients has been estimated to about 5% and prevalence of anti-HCV in OLP patients has been estimated as high as 38% and prevalence of HCV in India is 0.9–1.9%.[8] Considering the combined effect of betel-nut alkaloids and relation of aflatoxin with HCV, we plan to investigate the cases of OSMF with lichenoid lesion for HCV-RNA antibody titer.


   Methods Top


Correlation Between Liver Enzymes and HCV-RNA Antibody in Betel-Nut-Induced Lichenoid Lesions in OSMF: -A Cross-SectionalIn Vivo Study.

This study was conducted in Department of Oral Medicine & Radiology, Datta Meghe Institute of Medical Sciences (Deemed University), Sharad Pawar Dental College and Hospital, Sawangi (Meghe) Wardha, in association with Central Research Lab, Jawaharlal Nehru Medical College Sawangi (Meghe) Wardha, after approval from the Institutional Ethics Committee. A detailed clinical examination was carried out to identify oral lichenoid lesions in OSMF. The detailed history related to consumption of betel-nut was recorded and entered into structured Proforma.

Inclusion criteria

  • Patient above the age of 18 years up to 45 years clinically presented with oral lichenoid lesions in oral submucous fibrosis.


Exclusion criteria

  • Patient suffering from major systemic diseases
  • Cardiac disorder, liver disorder, diabetes Mellitus
  • Neuromuscular disorder, endocrine disorder
  • Patients under treatment of thiazides, beta-blockers, chloroquine.


Total 60 subjects were included and divided into following three groups. According to the patient coming to the department

  • Group I – 20 OSMF patients
  • Group II – 20 OSMF with lichenoid lesions patients
  • Group III – 20 Nonhabitual patients of betel-nut/tobacco/alcohol.


A 5 mL venous blood was collected under aseptic procedure for estimation of serum glutamate pyruvate (SGPT), serum oxaloacetic acid (SGOT), serum total bilirubin (T. B), serum alkaline phosphatase (ALP), and Hepatitis c virus RNA (HCV-RNA).

Following methods are used:

  1. Serum total bilirubin was estimated by modified Jendrassik and Grof
  2. Alanine and aspartate transaminase by IFCC method without pyridoxal phosphate
  3. Alkaline phosphatase by colorimetric
  4. Detection of HCV-RNA by Mini Vidas anti-HCV-RNA antibody.


Robonik kit reagents were used that were manufactured in India for estimation of glutamate oxaloacetate transaminase with reference No-0250, glutamate pyruvate – 0250, alkaline phosphatase – 0125, alkaline phosphatase – 0125, total bilirubin – 0250, and HCV-antibody by Vidas biomerux 69280.

Statistical analysis

All variables from the study will be statistically analyzed for the mean values, standard deviation, standard error, range, and 'P'-value. Evaluation of results and statistical analysis will be carried out using SPSS Software (Robonik Kit Manufactured In Mumbai, India).


   Results Top


The mean average age of OSMF patients was found to be 30.25 ± 8.61 years, OSMF with lichenoid lesion was found to be 33.10 ± 7.23 years, and of control group was found to be 31.05 ± 11.70 years.

Out of the total 20 patients, 85% were male with OSMF (M:F ratio 6:1), 90% were males with OSMF with lichenoid lesions (M:F ratio 9:1), and 70% were males in control group (M:F ratio 2.1:1).

Out of the total 20 patients, 65% had the habit of chewing kharra in OSMF group and 35% had the habit of chewing kharra in OSMF with lichenoid lesions [Figure 1].
Figure 1: Oral submucous fibrosis with lichenoid lesion

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Minimum duration of habit was 5 years and maximum was 25 years. The mean duration of habit in OSMF group was 4.45 ± 0.82 and OSMF with lichenoid lesions was 10.65 ± 6.98, which was statistically significant.

Statistically no significant difference was observed in distribution of patients according to buccal mucosa (right and left) in OSMF and OSMF with lichenoid (P = 0.54), retromolar region (P = 0.07), right and left labial mucosa (P = 0.14), hard and soft palate (P = 0.29), shrunken uvula (P = 1.00), circumoral fibrosis (P = 0.29), and floor of mouth (P = 0.54).

Mean value of interincisal opening for OSMF group was 24.05 ± 6.96, OSMF with lichenoid lesions was 26.15 ± 6.25, and control group was 41.05 ± 2.56. Statistically significant difference was found between groups and within groups (P = 0.0001).

Statistically no significant difference was found in groups with OSMF and OSMF with lichenoid lesions (P = 0.467) and significant difference was found with OSMF with control group and OSMF with lichenoid lesions (P = 0.0001).

Mean SGOT level in OSMF group was 43.30 ± 13.44 IU/L, in the OSMF with lichenoid lesions was 47.69 ± 10.49 IU/L, and in the control group was 31.26 ± 6.19 IU/L. Significant variation was found in serum SGOT levels among the three groups (P = 0.0001).

No significant difference was found between OSMF and OSMF with lichenoid lesions (P = 0.388) and with OSMF group and control group (P = 0.002), and with OSMF with lichenoid lesions with control group, the statistically significant difference was found to be (P = 0.0001).

Mean SGPT level in OSMF group was 44.85 ± 9.52 IU/L, OSMF with lichenoid lesions was 53.30 ± 8.11 IU/L, and control group was 34.23 ± 5.16 IU/L. Significant variation was found in serum SGPT levels between groups and within groups (P = 0.0001).

In OSMF and OSMF with Lichenoid lesions significant difference was found (P = 0.003) and in OSMF with control group (P = 0.0001) and OSMF with lichenoid lesions and control group was found to be significant (P = 0.0001).

Mean total bilirubin levels in patients with OSMF was found to be 3.35 ± 0.23 and in patients with OSMF with lichenoid lesions was found to be 3.66 ± 0.45 and in control group it was 2.23 ± 0.94. A significant difference was found between groups and within groups (P = 0.0001).

Nonsignificant difference was found in OSMF and OSMF with lichenoid lesions (P = 0.246) and significant difference was found in OSMF and control group (P = 0.0001) and in OSMF with lichenoid lesions and control group (P = 0.0001).

Mean alkaline phosphatase levels in patients with OSMF was found to be 121.20 ± 70.35, in patients with OSMF with lichenoid lesions was found to be 196.94 ± 95.84 and in control group was found to be 102.45 ± 27.71. A significant difference was found between groups and within groups (P = 0.0001).

Statistically significant difference was found with OSMF and OSMF with lichenoid lesions (P = 0.04) and in OSMF with lichenoid lesions and in control group (0.0001), whereas nonsignificant difference was observed in OSMF with control group (P = 0.679).

Mean HCV-RNA level in patients with OSMF group was 0.26 ± 0.23 and in OSMF with lichenoid lesions was 0.66 ± 2.20 and in control group was 0.18 ± 0.09. By using one-way analysis of variance (ANOVA), no significant difference was found between groups and within groups (P = 0.456).

Nonsignificant difference was found with OSMF and OSMF with lichenoid lesions (P = 0.596), in OSMF with control group (P = 0.976) and in OSMF with lichenoid lesions and control group (P = 0.469).

By using Pearson's correlation coefficient, negative correlation exists between duration of habit of disease and SGPT in OSMF with lichenoid lesions (r = −0.182 and P = 0.443).

Positive correlation exists between duration of habit of disease and SGOT in OSMF group (r = 0.091 and P = 0.702) and total bilirubin (r = 0.122 and P = 0.608) and alkaline phosphatase (r = 0.056 and P = 0.814) and HCV-RNA (r = 0.001 and P = 0.997). Negative correlation exists between duration of habit of disease and SGPT in OSMF group (P = 0.443).

The total billirubin in OSMF with lichenoid lesions (P = 0.816) with alkaline phosphatase in OSMF with lichenoid lesions (P = 0.010) and HCV-RNA in OSMF with lichenoid lesions (P = 0.312) [Graph 1].



Positive correlation exists between duration of habits of disease and SGOT in OSMF with lichenoid lesions (P = 0.826).


   Discussion Top


Oral submucous fibrosis is predominantly caused by the use of areca-nut.[1],[2] Besides being regarded as precancerous condition, it is a serious debilitating and progressive disease.[1],[2],[5],[8] A causal association between areca-nut chewing habit and OSMF, and lichenoid lesion and oral cancer has been strongly established.[1],[2],[4],[5],[8] In India, most of the habituals of betel-nut used tobacco. The frequency of chewing was directly correlated with OSMF.[9],[10],[11],[12],[13],[14] The mutagenic and carcinogenic properties of areca-nut have been extensively studied in variety of experimental studies.[2],[11],[13],[15] Areca-nut contains 5%–40% polyphenols and alkaloids including arecoline, arecadine, guvacine, and guvacoline.[1],[2]

In this study, Group I – OSMF, Group II – OSMF with lichenoid lesion, and Group III – control group constituted age- and sex-matched individuals. The mean age of all patients affected by OSMF was found to be 30.25 ± 8.61 years, which is comparable with the studies conducted by Hazarey et al.[16] [Table 1] and [Table 2]. Maximum numbers of patients (45%) in OSMF, that is, were between age of 20 and 29 years. Our study shows that high preponderance of OSMF in males (85%) and women were (15%) out of 20 patients. The male-to-female ratio was found to be 6:1. Similar findings were reported in previous studies.[17],[18] The mean age of all patients affected by OSMF with lichenoid lesion was found to be 33.10 ± 7.23 years with age range of 30–39 years and male-to-female ratio was 9:1, which is comparable with the study conducted by Daftary et al.[18]
Table 1: Details of oral submucous fibrosis and oral submucous fibrosis with lichenoid lesions fibrosis

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Table 2: Distribution of oral submucous fibrosis and oral submucous fibrosis with lichenoid lesion patients according to the type of habit

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Kharra is a local preparation of betel-nut mixed with tobacco and lime. Gutkha is the commercial form of mixture of betel-nut and tobacco. Most of the habituals were adapted to mixed habit of betel-nut chewing. In both Group I and Group II, kharra was the main habit. Thirteen (65%) patients with OSMF group and seven (35%) patients OSMF with lichenoid lesions consumed kharra daily. The mean duration of chewing betel nut in any form was 7.45 years with OSMF and 13.45 years in OSMF with lichenoid lesion. Zain et al.[11] stated that the total duration of chewing habit was not significantly correlated to OSMF. Daily consumption was more significant than total duration of the habit. The study conducted by Gupta et al. and Shah and Sharma[12],[13] reported that the habitual use of betel quid ≥5 years predisposes oral mucosa to oral premalignant disorders like OSMF. Instead of the duration of habit, type of habit or the form in which betel nut is chewed has been found to be of more significant in development and severity of OSMF. Mean duration of disease in Group I OSMF was 2.85 years and in Group II OSMF with lichenoid lesion was 3.60 years. All the habituals in Group I and Group II consumed betel-nut on daily basis with frequency in the range of three to eight times per day. In Group I, patients with habit of kharra was 75%, only areca-nut was 20%, and gutka was 15%. In Group II, kharra was 45%, areca-nut was 10%, and gutka was 10%.

The mean serum SGOT value was found to be 43.30 ± 13.44 IU/L in Group I, 47.69 ± 10.49 IU/L in Group II, and 31.26 ± 6.19 IU/L in Group III [Graph 2]. The mean serum SGPT values found in OSMF was 44.85 ± 9.52 IU/L, in OSMF with lichenoid lesions was 53.30 ± 8.11 IU/L, and control group was 34.23 ± 5.16 [Graph 3]. Anuradha and Shyamala Devi revealed significant increase in transaminase levels in OSMF patients.[19] Human tissue harbors the potential to bioactivate the safrole in betel quid to its corresponding DNA adducts, in the liver. Betel quid chewing and areca-nut derived nitrosoamines becomes genotoxic to hepatocyte and hence produces liver cirrhosis and liver cancer.[5],[6],[15],[19],[20],[21],[22],[23],[24]



Value of SGOT, SGPT, TB, HCV-RNA, and ALP are raised in [Graph 4] OSMF with lichenoid lesion, which are statistically significant compared with OSMF and control group using one-way ANOVA. SGOT (P = 0.0001), SGPT (P = 0.0001), TB (P = 0.0001), ALP (P = 0.0001), and HCV-RNA (P = 0.0001).



Indian study revealed that 37.5% betel-nut samples were infested with Aspergillus flavus.[5] Aflatoxin is metabolized in liver and forms aflatoxin–albumin adducts, which may be responsible for mutagenesis in liver. Hence, the liver damage in betel-nut habituals could be caused by the combined effect of both aflatoxin and betel nut alkaloids. Aflatoxin and betel-nut alkaloids target the hepatocytes results in increased serum transaminases, total bilirubin, and alkaline phosphatase, which are marker for liver damage.[6],[20] In this study, all the patients in Group I and Group II were regular daily user of betel-nut in any form responsible for continuous release of aflatoxin from the betel nut chewing, maintaining the serum aflatoxin level and forming the albumin adduct. As duration of disease showed negative correlation with HCV-RNA in OSMF (r = −0.269 and P = 0.251) and OSMF with lichenoid lesions (r = −0.307 and P = 0.187). Negative correlation with HCV-RNA with duration of disease and habit was due to the fact that once the host is infected and positive for circulating antibody, it further does not affected by duration of habit and disease [Graph 5].



Metabolic activation by cytochrome P-450-dependent mono-oxygenases (liver microsomes) is required for AFB1 to exert its toxic, mutagenic, and carcinogenic effects. Various subgroups of cytochrome P-450 are involved in conversion of AFB1 to several metabolites.[4],[25] AFB1 epoxide is generally accepted as active electrophilic form of AFB1 that may attack nucleophilic nitrogen, oxygen, and sulfur heteroatoms in cellular constituents. These highly reactive substances may combine with DNA bases such as guanine to produce alterations in DNA. Formation of these adducts disrupts the normal working process of the cell and, in cases of DNA adducts, can ultimately lead to loss of control over cellular growth and division.

Faroombi[4] showed synergistic interaction with activation of cytochrome P450, which leads to metabolism of inactive AFB1 to the mutagenic. AFB1-8, 9-epoxide binds to liver cell DNA, and abrogates normal function of P53, in cell cycle control, DNA repair and apoptosis as well as generation of reactive oxygen species. By sensitizing cells to AFB1 and inducedP 53 and 249ser, mutations also convert G to T transversion at codon 249 and thus contribute to multistep process of hepatocarcinogenesis.

Lin et al.[26] discussed that arecoline, arecaidine, and other BQ-related metabolites may exist at nano-gram concentrations in human blood and the level of arecoline is significantly associated with the quantity of BQ used. The effects of polymorphisms on BQ chewing-related symptoms, including cancer of the oral cavity, pharynx oral premalignant disorders (OPMDs) among xenobiotic metabolizing enzymes CYP1A1, CYP2A6, and CYP2E1 may activate sreca-nut-derived nitrosamines.

Vandermeij[27] conducted study on 67 OLP and 125 oral lichenoid lesion (OLL) and reported significant difference between the two; these groups of patients were followed 7.6- to 96.9-month period. During follow-up period, four patients with OLL reported with a malignant transformation (142-fold increase) 0.71% year. There were no malignant cases reported from OLP group. Study by Bombeccari et al.[28] showed significant association of OLP and malignant conversion with incidence ratio of 17.7 (95% of confidence interval 8.8–35.3).

Van der, Meij EH[27] reported a significant epithelial dysplasia in OLP with 142-fold increase malignant transformation in oral lichenoid lesion. This study was conducted in OSMF and OSMF with lichenoid lesion patients, in which betel-nut alkaloid and aflatoxin is responsible for the liver dysfunction. OSMF and OSMF with lichenoid lesion showed a significant correlation between the liver enzymes, SGOT, SGPT, ALP, and total bilirubin with increase in HCV-RNA antibody titre, in both OSMF and OSMF with lichenoid lesion compared with control subjects. These patients should be considered high-priority candidates for malignant transformation. All OSMF and OSMF with lichenoid lesion should be consider for candidates of liver damage and must be started with hepatoprotective agent.


   Conclusions Top


The present correlation of transaminase, total bilirubin, alkaline phosphatase, and HCV-RNA antibody titer in OSMF and OSMF with lichenoid lesion is suggestive of liver damage. This liver damage is due to betel-nut alkaloid and infestation of betel-nut with Aspergillus flavus. Combined synergistic and additive effects of alkaloids and aflatoxin may be responsible for aggravation of liver damage and immunosuppression.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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