|Year : 2019 | Volume
| Issue : 4 | Page : 315-319
Assessment of risk of liver fibrosis in areca nut habitual by ultrasound elastography
Suwarna Dangore-Khasbage, Rahul Bhowate
Department of Oral Medicine and Radiology, Sharad Pawar Dental College, Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra, India
|Date of Submission||10-Nov-2019|
|Date of Decision||24-Nov-2019|
|Date of Acceptance||03-Dec-2019|
|Date of Web Publication||16-Jul-2020|
Dr. Suwarna Dangore-Khasbage
Sharad Pawar Dental College, DMIMSU, Wardha, Maharashtra
Source of Support: None, Conflict of Interest: None
Purpose: The purpose of this study was to assess the risk of liver fibrosis in areca nut (AN) habitual by ultrasound elastography. Materials and Methods: This case–control study included sixty individuals, which were equally divided into four groups. Among these, 15 belonged to the control group, whereas 45 were chronic AN chewers either suffering from habit-induced oral disease or not suffering from habit-induced oral disease. All of them were assessed for oral health status by recording habit history and oral examination findings. Liver status was assessed by conventional ultrasonography and elastography. Results: Ultrasonography revealed the presence of liver fibrosis in 6 (10%) participants. Among these participants, 3 (50%) were suffering from oral submucous fibrosis (OSMF), 2 (33%) had OSMF with oral squamous cell carcinoma, and 2 (17%) were AN habitual only. On elastography, FibroScan values were observed to be higher in liver fibrosis-diagnosed participants though the difference between habitual and nonhabitual was not significant (NS) (P = 0.103, NS). Conclusion: On assessment of liver status, liver fibrosis was diagnosed in 10% AN habitual. This finding is alarming one and needs a specific concern as these habitual participants were totally asymptomatic and unaware of their liver status.
Keywords: Areca nut, elastography, liver fibrosis, ultrasonography
|How to cite this article:|
Dangore-Khasbage S, Bhowate R. Assessment of risk of liver fibrosis in areca nut habitual by ultrasound elastography. J Datta Meghe Inst Med Sci Univ 2019;14:315-9
|How to cite this URL:|
Dangore-Khasbage S, Bhowate R. Assessment of risk of liver fibrosis in areca nut habitual by ultrasound elastography. J Datta Meghe Inst Med Sci Univ [serial online] 2019 [cited 2020 Aug 4];14:315-9. Available from: http://www.journaldmims.com/text.asp?2019/14/4/315/289854
| Introduction|| |
Areca nut (AN), commonly called betel nut or supari, is a fruit of areca catechu palm tree, which is native of South Asia and the Pacific Islands. AN contains water 30%, protein 5%, fat 3%, carbohydrate 47%, and arecoline 0.2%–0.7%, one of the major alkaloids. Among these constituents, alkaloids, flavonoids, and tannins are the proven carcinogenic contents of AN.
Arecoline is the main agent responsible for fibroblast proliferation. Under the influence of slaked lime, arecoline gets hydrolyzed to arecadine, which has pronounced effects on fibroblasts., Areca flavonoids, tannins, and catechins can cause increased fibrosis by forming a more stable and nonsoluble collagen structure by inhibiting collagenase enzyme activity., AN contains a significant amount of Cu that also takes part in fibrotic conditions by increasing lysyl oxidase activity. Hence, the overall effect of AN is fibrosis of the tissues. Accordingly, a number of studies reported the role of AN in oral fibrotic conditions such as oral submucous fibrosis (OSMF) as well as in oral squamous cell carcinoma (OSCC).,,,, Nevertheless, AN-induced fibrosis is not limited to oral tissues; however, it may affect other vital organs such as liver leading to liver fibrosis. However, to our knowledge, scanty literature is available related to the risk of liver fibrosis in AN habitual. Thus, the present study was undertaken to assess the risk of liver fibrosis in AN habitual by ultrasound elastography.
It is well known that liver biopsy is a gold standard method and is traditionally used for evaluation of liver damage. However, it has got many limitations which confine its utility.
These limitations of the liver biopsy have motivated researchers for using noninvasive methods such as ultrasonography and elastography for assessing liver fibrosis. Ultrasonography is a noninvasive imaging modality, frequently used for routine liver fibrosis screening.,, It has low sensitivity and specificity but reported to have 80% diagnostic accuracy in liver fibrosis. Elastography which is often referred to as liver ultrasonographic elastography was also used as an adjuvant investigation in this study. A number of studies are there which evaluated the diagnostic accuracy of elastography in the measurement of liver fibrosis by comparing the elastography with biopsy results and proved elastography useful for liver fibrosis.,,
| Materials and Methods|| |
This Institutional Ethics Committee approved a case–control study including 60 individuals, which were divided into four equal groups of 15 each: Group I – control (nonhabitual individuals), Group II – chronic AN habitual, Group III – chronic AN habitual and suffering from OSMF, and Group IV – chronic AN habitual and suffering from OSMF with OSCC.
Inclusion criteria were as follows: (i) individuals within the age range of 20–60 years irrespective of gender, (ii) nonhabitual as well as chronic AN habitual (duration of more than 12 months) reporting for routine dental checkup and consented to participate, and (iii) chronic AN habitual suffering from only OSMF and OSMF with OSCC.
Exclusion criteria were as follows: (i) individuals above 60 years of age, (ii) patients taking treatment for OSMF or OSCC, (iii) patients having tobacco or alcohol consumption habit also along with AN chewing, and (iv) patients suffering from systemic diseases such as hepatitis, anemia, malaria, chicken guinea, dengue, and severe intestinal parasitic infections as these conditions may cause liver damage. Patients with a history of chronic liver disease to their first-degree relatives. All the participants were counseled about the purpose of the study and method to be used, and written consent was obtained from each one of them.
The patients were explained about the purpose of the study, and written consent was obtained before the examination. A detailed medical and habit history was recorded. Careful oral examination was performed for each patient to diagnose OSMF or OSCC. Then, the same patients were evaluated for liver status by ultrasonography and elastography. A senior radiologist performed the procedure by an ultrasound machine (Core vision, Diagnostic Ultrasound System, Model SSA-350 A, Toshiba, Japan) with a 2–5 MHz convex array transducer (low-frequency probe) and a 5–12 MHz convex array transducer (high-frequency probe). Live fibrosis assessment and scoring (mild, moderate, and severe) was done based on surface nodularity, liver edge, and parenchymal echotexture by following the previously published scoring system. Elastography was performed by ECHOSENS FibroScan 402 Transient Elastography Machine (Paris, France). As the literature suggests, ten measurements were obtained, and the median of these was reported as final. Elastography scores were calculated as described by Castéra et al. The data so obtained were then tabulated and statistically analyzed using relevant statistical tests.
Ethical clearance was obtained from the Institutional Ethical Committee of SPDC, Sawangi (Meghe), Wardha, on 20nd April 2019. With ethical clearance no DMIMS(DU)/IEC/2019-20/339.
| Results|| |
Sixty AN habitual participants were assessed for liver fibrosis in the present study. The age-wise and gender-wise distribution of patients in all the groups is shown in [Graph 1] and [Graph 2], respectively. The youngest participant in the study was 21 years and the eldest was 57 years old. The mean age of patients was 38.63 ± 8.26 in Group I, 39 ± 23.77 in Group II, 34.16 ± 9.95 in Group III, and 49.06 ± 10.16 in Group IV. Among all, 35 participants were male and 25 were female.
With reference to duration and frequency of habit, it was observed that the mean duration of habit in years was 18.6 ± 8.77 years (minimum duration: 7 years and maximum duration: 32 years), whereas the mean of frequency of habit per day was 7.86 ± 1.76 (minimum: 3 times/day and maximum: 11 times/day).
Ultrasound examination of the liver revealed the presence of fibrosis in 6 (10%) of total 60 participants, as shown in [Table 1]. Among them, 7% (no. 1/15) were AN habitual, 20% (no. 3/15) patients were suffering from OSMF and 13 from Group III, that was; patients suffering from OSMF with OSCC were diagnosed to have liver fibrosis, results were statistically not significant (NS) (P = 0.27, NS).
A correlation between the stage of OSMF and liver fibrosis showed that all the OSMF patients (3) diagnosed to have liver fibrosis were suffering from an advanced stage of oral fibrosis, as shown in [Table 2].
|Table 2: Correlation between the stage of oral submucous fibrosis and liver fibrosis|
Click here to view
The present study also assessed liver fibrosis by elastography as an adjuvant investigation. Among the Ultrasound (USG) diagnosed six liver fibrosis patients, four showed significant fibrosis on FibroScan screening as FibroScan values were between 7 and 9.5 kilopascals (kPa), whereas two had mild fibrosis (FibroScan values were below 7 kPa). The mean of FibroScan values in different groups was within the normal limit but observed to be comparatively higher in the OSMF group, as compared to the other three groups, results of which were statistically NS, as shown in [Table 3] (P = 0.103, NS).
| Discussion|| |
Liver fibrosis is a part of the structural and functional alterations in most chronic liver diseases. It is one of the main prognostic factors as the amount of fibrosis is correlated with the risk of developing cirrhosis and liver-related complications in viral and nonviral chronic liver diseases. The stage of liver fibrosis is important to determine prognosis and surveillance and to prioritize treatment and potential for reversibility. The studies have shown that regression of fibrosis is possible with treatment of the underlying condition., Therefore, detection and management of liver damage in the initial stage like liver fibrosis in AN habitual can protect an individual from its various life-threatening complications such as cirrhosis, hepatocellular carcinoma, and portal hypertension., Thus, the present study was designed to assess liver fibrosis in AN habitual.
In the present study, 10% (6 of 60) participants were diagnosed to have liver fibrosis on USG evaluation, and all of them were belonging to study groups. This represents the role of AN consumption in liver fibrosis; findings are comparable to the previous study by Saawarn et al. However, the percentage of liver fibrosis in AN habitual was more in their study that was 19%, and of these, 75% were OSMF patients, whereas 25% were only AN chewers. In the present study, 50% were OSMF patients, 33% were suffering from OSMF with OSCC, and 17% were AN chewers without any clinical oral disease. Wang et al. also reported that substance use habit including AN consumption increases the risk of hepatocellular carcinoma as compared to those who had no habit with a relative risk of 3.43.
In the present study, the mean duration of habit in years was 18.6 ± 8.77 years; findings are comparable to the previous studies by Tsai et al.,, in which chewing betel quid for more than 20 years was found to be an independent risk factor for hepatocellular carcinoma; however, in the present study, the duration of habit ranges from 8 to 32 years.
Similarly, Lin et al. observed a significant association between habitual betel quid chewing and liver disease risk, but they stated that their observations might be partly attributable to alcohol drinking or cigarette smoking because of significant correlations among substance-use habits. In the same way, Sun et al. suggested a greater risk of hepatocellular carcinoma due to the combined effect of hepatitis C virus infection and betel quid chewing than of either factor alone with a synergy index of 4.2.
There are a variety of mechanisms describing the role of betel quid chewing in causation of liver damage. Few of which are as under.,,,,
(1) An exposure of fibroblasts to the extracts of betel has been suggested to trigger collagen synthesis and stabilize collagen fibrils. (2) A significant amount of reactive oxygen species production is induced by AN extract. (3) Oxidative reaction is associated with fibrogenesis occurring in the liver. (4) Fibrogenesis stimulate free radical reactions either directly or through inflammatory stimuli. (5) Fibrotic liver injury results in activation of the hepatic stellate cell which undergoes a phenotypic change to a proliferative myofibroblast-like cell that synthesizes excess interstitial collagens and other matrix components. (6) Long-term betel-quid feeding to animals can develop chronic hepatocyte necroinflammation. (7) AN has shown to have a high copper content that leaches into saliva and gets circulated in the oral cavity. Copper-dependent lysyl oxidase enzyme upregulates the cross-linkage of collagen and elastin fibers that cause fibrosis of submucosal tissues. A similar phenomenon might be responsible for liver fibrosis.
However, Singroha and Kamath stated that even long-term chewing of AN is not hepatotoxic because of the antioxidant activity of the tannins present in the AN and the regenerative capacity of the liver. Another previous study too indicates the anticarcinogenic role of betel leaf extracts in tobacco-induced cancer in rats.,,,,,
Overall results of the present study indicated an increased risk of liver fibrosis in AN habitual as 10% of the habitual participants had liver fibrosis. The limitation of the present study is small sample size.
| Conclusion|| |
The presence of liver disease in 10% AN habitual, who were asymptomatic and thus unaware of their liver status, should be considered as an alarm to them to give up the habit and direction to oral physicians to evaluate AN habitual for liver status and to treat them if necessary.
We wish to thank Datta Meghe Institute of Medical Sciences for permitting to do this research and the Dean and Vice-Dean of Sharad Pawar Dental College for their kind help during this study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Adediji JA, Eze GI, Ehimigbai AR. Histological changes induced by aqueous extract of areca nut (areca catechu) on the liver of adult wistar rats. J Pharm Sci Innov 2015;4:258-61.
Tilakaratne WM, Klinikowski MF, Saku T, Peters TJ, Warnakulasuriya S. Oral submucous fibrosis: Review on aetiology and pathogenesis. Oral Oncol 2006;42:561-8.
Nair U, Bartsch H, Nair J. Alert for an epidemic of oral cancer due to use of the betel quid substitutes gutkha and pan masala: A review of agents and causative mechanisms. Mutagen 2004;19:251-62.
Prabhu RV, Prabhu V, Chatra L, Shenai P, Suvarna N, Dandekeri S. Areca nut and its role in oral submucous fibrosis. J Clin Exp Dent 2014;6:e569-75.
Meghji S, Scutt A, Cannif JP, Harvey W, Phillipson JD. Inhibition of collagenase activity by areca nut tannins: A mechanism of collagen accumulation in oral submucous fibrosis? J Dent Res 1982;61:545.
Shah G, Chaturvedi P, Vaishampayan S. Arecanut as an emerging etiology of oral cancers in India. Indian J Med Paediatr Oncol 2012;33:71-9.
] [Full text]
Trivedy C, Baldwin D, Warnakulasuriya S, Johnson NW, Peters TJ. Cu content in areca catechu (betel nut) products and oral submucous fibrosis. Lancet 1997;340:1447.
Hande AH, Chaudhary MS, Gawande MN, Gadbali AR, Ade PR, Bajaj S, et al
. Oral submucous fibrosis: An enigmatic morpho-insight. J Can Res Ther 2019;14:63-9.
Kadashetti V, Shivakumar KM, Chaudhary M, Patil S, Gawande M, Hande A. Influence of risk factors on patients suffering from potentially malignant disorders and oral cancer. A case control study. J Oral Maillofac Pathol 2017;21:455-6.
Lin YS. Ultrasound evaluation of liver fibrosis. J Med Ultrasound 2017;25:127-9.
Allan R, Thoirs K, Phillips M. Accuracy of ultrasound to identify chronic liver disease. World J Gastroenterol 2010;16:3510-20.
Gerstenmaier JF, Gibson RN. Ultrasound in chronic liver disease. Insights Imaging 2014;5:441-55.
Tchelepi H, Ralls PW, Radin R, Grant E. Sonography of diffuse liver disease. J Ultrasound Med 2002;21:1023-32.
D'Onofrio M, Martone E, Brunelli S, Faccioli N, Zamboni G, Zagni I, et al
. Accuracy of ultrasound in the detection of liver fibrosis in chronic viral hepatitis. Radiol Med 2005;110:341-8.
Barr RG, Ferraioli G, Palmeri ML, Goodman ZD, Tsao GG, Rubin J, et al
. Elastography assessment of liver fibrosis: Society of radiologists in ultrasound consensus conference statement. Radiol 2015;276:845-61.
Tajiri K, Kawai K, Sugiyama T. Strain elastography for assessment of liver fibrosis and prognosis in patients with chronic liver diseases. J Gastroenterol 2017;52:724-33.
Robertis RD, D'Onofrio M, Demozzi E, Crosara S, Canestrini S, Mucelli RP. Noninvasive diagnosis of cirrhosis: A review of different imaging modalities. World J Gastroenterol 2014;20:7231-41.
Nishiura T, Watanabe H, Ito M, Matsuoka Y, Yano K, Daikoku M, et al
. Ultrasound evaluation of the fibrosis stage in chronic liver disease by the simultaneous use of low and high frequency probes. Br J Radiol 2005;78:189-97.
Castéra L, Vergniol J, Foucher J, Le Bail B, Chanteloup E, Haaser M, et al
. Prospective comparison of transient elastography, fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterol 2005;128:343-50.
Hsiao TJ, Liao HW, Hsieh PS, Wong RH. Risk of betel quid chewing on the development of liver cirrhosis: A community-based case-control study. Ann Epidemiol 2007;17:479-85.
Arthur MJ. Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C. Gastroenterol 2002;122:1525-8.
Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005;115:209-18.
Saawarn N, Chand PH, Gharote H, Nair P, Naik S, Srivasatava H, et al
. Liver fibrosis in OSMF patients and AN chewers: An ultrasonographic study. Int J Adv Res 2016;4:280-3.
Wang LY, You SL, Lu SN, Ho HC, Wu MH, Sun CA, et al
. Risk of hepatocellular carcinoma and habits of alcohol drinking, betel quid chewing and cigarette smoking: A cohort of 2416 HBsAg-seropositive and 9421 HBsAg-seronegative male residents in Taiwan. Cancer Causes Control 2003;14:241-50.
Tsai JF, Chuang LY, Jeng JE, Ho MS, Hsieh MY, Lin ZY, et al
. Betel quid chewing as a risk factor for hepatocellular carcinoma: A case-control study. Br J Cancer 2001;84:709-13.
Tsai JF, Jeng JE, Chuang LY, Ho MS, Ko YC, Lin ZY, et al
. Habitual betel quid chewing as a risk factor for cirrhosis: A case-control study. Med (Baltimore) 2003;82:365-72.
Tsai JF, Jeng JE, Chuang LY, Ho MS, Ko YC, Lin ZY, et al
. Habitual betel quid chewing and risk for hepatocellular carcinoma complicating cirrhosis. Med (Baltimore) 2004;83:176-87.
Lin HH, Wang LY, Shaw CK, Cheng ML, Chung WK, Chiang HJ, et al
. Combined effects of chronic hepatitis virus infections and substance-use habits on chronic liver diseases in Taiwanese aborigines. J Formos Med Assoc 2002;101:826-34.
Sun CA, Wu DM, Lin CC, Lu SN, You SL, Wang LY, et al
. Incidence and cofactors of hepatitis C virus – Related hepatocellular carcinoma: A prospective study of 12,008 men in Taiwan. Am J Epidemiol 2003;157:674-82.
Keng VW, Largaespada DA, Villanueva A. Why men are at higher risk for hepatocellular carcinoma? J Hepatol 2012;57:453-4.
Sarma AB, Chakrabarti J, Chakrabarti A, Banerjee TS, Roy D, Mukherjee D, et al
. Evaluation of pan masala for toxic effects on liver and other organs. Food Chem Toxicol 1992;30:161-3.
Singroha K, Kamath VV. Liver function tests as a measure of hepatotoxicity in an chewers. J Dent Res Rev 2016;3:60-4. [Full text]
Padma PR, Lalitha VS, Amonkar AJ, Bhide SV. Anticarcinogenic effect of betel leaf extract against tobacco carcinogens. Cancer Lett 1989;45:195-202.
Phatak S, Marfani G. Galactocele Ultrasonography and Elastography Imaging with Pathological Correlation. J Datta Meghe Inst Med Sci Univ 2018;13:1-3. Available from: https://doi.org/10.4103/jdmimsu.jdmimsu_51_18
. [Last accessed on 2019 Aug 22].
Gulve SS, Phatak SV. Parathyroid Adenoma: Ultrasonography, Doppler, and Elastography Imaging. J Datta Meghe Inst Med Sci Univ 2019;14:47-9. Available from: https://doi.org/10.4103/jdmimsu.jdmimsu_91_18
. [Last accessed on 2019 Aug 22].
Madurwar KA, Phatak SV. Benign Fibrous Histiocytoma of Male Breast: Ultrasonography, Doppler, and Elastography Imaging with Pathological Correlation. J Datta Meghe Inst Med Sci Univ 2019;14:103-5. Available from: https://doi.org/10.4103/jdmimsu.jdmimsu_44_18
. [Last accessed on 2019 Aug 22].
Marfani G, Phatak SV, Madurwar KA, Samad S. Role of Sonoelastography in Diagnosing Endometrial Lesions: Our Initial Experience. J Datta Meghe Inst Med Sci Univ 2019;14:31-5. Available from: https://doi.org/10.4103/jdmimsu.jdmimsu_89_18
. [Last accessed on 2019 Aug 22].
Phatak S, Shrivastav D, Marfani G, Daga S, Madurwar K, Samad S. Transvaginal Sonography and Elastography Evaluation of Ectopic Pregnancy. J Datta Meghe Inst Med Sci Univ 2019;14:86-9. Available from: https://doi.org/10.4103/jdmimsu.jdmimsu_13_19
. [Last accessed on 2019 Aug 22].
[Table 1], [Table 2], [Table 3]