ORIGINAL RESEARCH
Year : 2023 | Volume
: 15 | Issue : 1 | Page : 52--58
Hepatitis C associated oral lesions: A hospital-based retrospective case control study in Egypt
Radwa M Ismail1, Amira R Elansary2, Ola M Ezzatt3, Mohamed G Hamed4, Yasmine Gamil5,
1 Department of Oral Medicine, Periodontology, Oral Diagnosis and Oral Radiology. Faculty of Oral and Dental Surgery, Misr University for Science and Technology (MUST), Cairo, Egypt
2 Department of Internal Medicine, Faculty of Medicine, Misr University for Science and Technology (MUST), Cairo, Egypt
3 Department of Oral Medicine, Periodontology, Oral Diagnosis and Radiology, Faculty of Dentistry, Ain Shams University, Cairo, Egypt
4 Department of Otorhinolaryngology, Faculty of Medicine, Helwan University, Cairo, Egypt
5 Department of Oral Medicine, Periodontology and Oral Diagnosis. Faculty of Dentistry, Modern University of Information and Technology (MTI), Cairo, Egypt
Correspondence Address:
Dr. Radwa M Ismail
Department of Oral Medicine, Periodontology, Oral Diagnosis and Oral Radiology. Faculty of Oral and Dental Surgery, Misr University for Science and Technology (MUST), Cairo
Egypt
Abstract
Aim: Investigate the association of hepatitis C virus (HCV) infection on incidence of various oral lesions in a sample of Egyptian population. Materials and Methods: This case control observational retrospective study was conducted on outpatients’ clinics of a University Hospital. The predicted total sample size (n) was 100 with 1:1 ratio by using G*Power (version 3.1.9.79). In which, incidence and frequency of different oral manifestations in 50 HCV patients (cases) were compared to that of 50 healthy individuals(controls). Demographic and clinical data were collected using a structured questionnaire. Frequencies of findings were compared and analyzed using Fisher’s exact test, and regression analysis was performed to ascertain the effects of hepatitis C as well as age, sex and diabetes mellitus on the likelihood of different oral findings. Results: The oral mucosal signs and symptoms were generally more frequent among HCV compared to healthy controls. The frequency was statistically significant higher in HCV patients regarding xerostomia (40%), altered taste (24%) and oral lichen planus (20%), but insignificant regarding atrophic tongue (18%), oral pigmentation (14%) and pallor (10%). The presence of HCV was significantly associated with increased odds of xerostomia (P = 0.028, OR=4.3), oral pigmentations (P = 0.013, OR=12.6) and atrophic tongue (P = 0.039, OR=7.8). While other predictors had no significant effects on any of oral findings. Conclusion: In a hospital-based sample of Egyptian population; Xerostomia, altered taste and oral lichen planus were significantly frequent with HCV infection in comparison to healthy individuals. While xerostomia, oral pigmentations and atrophic tongue were associated with HCV.
How to cite this article:
Ismail RM, Elansary AR, Ezzatt OM, Hamed MG, Gamil Y. Hepatitis C associated oral lesions: A hospital-based retrospective case control study in Egypt.J Int Oral Health 2023;15:52-58
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How to cite this URL:
Ismail RM, Elansary AR, Ezzatt OM, Hamed MG, Gamil Y. Hepatitis C associated oral lesions: A hospital-based retrospective case control study in Egypt. J Int Oral Health [serial online] 2023 [cited 2023 Jun 1 ];15:52-58
Available from: https://www.jioh.org/text.asp?2023/15/1/52/370747 |
Full Text
Introduction
Hepatitis C Virus (HCV)is Hepatotropic RNA virus which can induce chronicity associated with various prolonged complications.[1] It was reported by the Egyptian demographic health survey in 2015 that 10.0% 0f Egyptian papulation have active HCV infection and this percentage is 1.4% more than that of the global levels that were estimated by World Health Organization (WHO).[2] Other, meta-analysis in 2018 reported that 11.9% of Egyptian population had HCV-antibody and it is the highest reported prevalence of HCV globally.[3]
Chronic hepatitis C (CHC) patients are subjected to serious life threatening conditions mainly liver cirrhosis and hepatocellular carcinoma.[4] However, in the course of chronic HCV infection, about 70% of patients may develop first or only clinical sign of infection in the form of extrahepatic manifestations.[5] Moreover, extrahepatic tissues might act as reservoir for HCV thus could affect transmission, morbidity and treatment.[6] Several epidemiologic studies had reported various HCV extrahepatic manifestations including type 2 diabetes mellitus, glomerulopathies, cryoglobulinemia, non-Hodgkin lymphomas (NHL), cardiovascular disease, neurological and psychiatric disease and rheumatic diseases,[5],[7] as well as oral manifestations.[6],[8]
Hepatitis C virus is frequently linked with malignant or potentially malignant as well as variable benign oral lesions and could be even a triggering factor of some of those lesions or at least influence their outcome.[6] HCV may induce a low-grade chronic systemic inflammation that may cause the development of extrahepatic manifestations.[9]
Different oral manifestations have been reported in patients with HCV including atrophic tongue, mucosal membrane jaundice, xerostomia, altered taste and candidiasis.[10],[11] The association was very strong for oral lichen planus, while for Sjogren ’syndrome and sialadenitis it was strongly suspected.[9] Squamous cell carcinoma was also reported in HCV patients as the most common oral malignancy that can induced as a result of HCV chronicity complications.[12]
Identification of extrahepatic symptoms of HCV infection and clarifying the possible relation between oral conditions and HCV could be helpful in early diagnosis mainly in asymptomatic patients and indicates the significance of dental care delivery for people with hepatitis C infection.[13]
A review of the literature showed several published studies addressing the frequency of different oral lesions in hepatitis C patients globally and among various populations.[7],[8],[14],[15],[16]
Despite high prevalence of this diseases in Egypt, to the best of authors’ knowledge, only one published case control study has evaluated and compared the oral health status of patients with HCV to healthy controls in a sample of the Egyptian population[17] and so the objective of this study was to determine the influence and association of hepatitis C virus (HCV) infection on incidence of various oral and mucosal lesions in a sample of Egyptian population attending a university hospital.
The null hypothesis was that HCV infection had an extrahepatic manifestation that could affect oral cavity.
Materials and Methods
Study design
It is a case-control retrospective observational single center study.
Sample size estimation
Sample size calculation was performed using G*Power (version 3.1.9.79). Power analysis was designed to have adequate power to apply a two-sided statistical test of the null hypothesis that there is no difference between cases and control groups. By adopting an alpha level of (0.05) a beta of (0.2) i.e., power=80% and a critical (z) value of (1.96) calculated based on the results of Zahed M., et al.,[18] the predicted total sample size (n) was 100 and a case–control ratio of 1:1, so that the minimum required sample size per group was 50 participants.
Subjects
This observational retrospective case control study was conducted at 100 outpatients’ and dental clinics in a hospital university in Egypt over 10 months period from March 2021 till January 2022.
A total of 100 Egyptian adult participants of both genders with age range from 20–70 years were randomly recruited for the study, 50 chronically HCV infected patients were recruited for the (Case) group, and 50 clinically healthy participants were recruited for the (Control) group according to inclusion and exclusion criteria and according to HCV test they were allocated to one of both groups (case and control).
Inclusion criteria
HCV infected egyptian patients with a positive (anti- HCV test) regardless of the cause of infection, while clinically healthy participants with negative (anti- HCV test) based on national screening health survey performed in Egypt, no history of liver disease, or any other chronic debilitating illness.
Exclusion criteria
Patients who were receiving antiviral treatment, patients with acute hepatitis, those with hepatitis B or HIV virus co-infection and those with advanced liver failure or hepatocellular carcinoma were excluded from this group. Participants with history of smoking or alcoholism, as well as history of an intervention, medication or condition that could affect the oral mucosa or health were excluded from the study.
Diagnosis of Participants
Patients were selected and recruited to one of both groups according to HCV test whether its positive that indicate that patients with active hepatitis C or negative. Then extra laboratory investigations include Aspartate aminotransferase (AST) and alanine transaminase (ALT) enzymes level ratio were made for patients with positive test to indicate liver cirrhosis or alcoholic hepatitis. AST/ALR ratio above 1% is excluded from the study. Glycated hemoglobin test was made for both groups to detect glucose levels. Patients with moderatly controlled diabetes mellitus (glycated hemoglobin test equal or more than 8%) were excluded from the study. After patient selection explanation of the purpose of the study, the optional participation in the study with the confirmation of the confidentiality of the information were declared to all the participants. Participant’s agreements were taken by signing the informed consent.
Data collection
Nationality to ensure that he/she is egyptian according to inclusion criteria, personal data including age, and socioeconomic status, as well as medical and medication history and patient’s laboratory investigations were recorded by the investigators for all eligible participants using health questionnaire. Oral or mucosal symptoms reported by the patients were recorded. Particularly, symptoms of xerostomia were documented by assessing response with yes/no to following questions: Does the amount of saliva in your mouth seem to be too little, too much, or you do not notice it? Do you have any difficulty in swallowing? Does your mouth feel dry when eating a meal? Do you sip liquids to aid in swallowing dry food?.[19]
Detailed oral and mucosal examination were performed at dental clinics by the specialist dentist who didn’t know the allocation of patients in which group, using simple disposable dental examination instruments. Ulcers, erosions, pigmentations and exophytic lesions, as well as, hyperkeratosis and erythematous mucosa and other atypical variations of the mucosa were diagnosed according to the history and clinical criteria based on World Health Organization (WHO) guide to epidemiology and diagnosis of oral mucosal diseases.[20] If indicated, a biopsy for histopathological evaluation were performed to reach a definitive diagnosis of mucosal lesions. Normal variation such as geographic tongue and physiologic pigmentation, as well as dental caries, endodontic lesions and periodontal diseases were excluded from the study. No bias was detected in this study as cases were selected according to HCV test (anti-HCV positive or negative test) and the detailed oral examination was done by blinded specialist dentist that didn’t know the allocation of each patient in which group.
Statistical analysis
The frequency of various oral manifestations in hepatitis C (Cases) and in clinically healthy (Control) participants were recorded, tabulated, and documented to be analyzed at the end of the study.
Categorical data were presented as frequency and percentage values and were analyzed using Fisher’s exact test. Numerical data were presented as mean and standard deviation values and were checked for normality using Shapiro-Wilk test. Data showed parametric distribution and were analyzed using independent t-test. Binomial logistic regression models were used for multivariate analysis. The significance level was set at P < 0.05 within all tests. Statistical analysis was performed with R statistical analysis software (version 4.1.2 for Windows). (R Core Team (2022). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/.
Results
One hundred subjects participated in the study. The difference between both groups was not statistically significant regarding sex distribution. However, the mean age of the cases was significantly higher than that of the controls (P < 0.001) [Table 1].{Table 1}
The mean duration of known HCV infection was 2.51 ± 3.71 years. Infection sources of HCV in cases group included possible percutaneous or mucosal exposure (23 cases), blood transfusions (11 cases), drug abuse (2 cases), and sexual intercourse (5 cases). However, the source of infection was not identified in 9 patients. Clinical manifestations of HCV were present in 65% of patients including nonspecific symptoms, such as malaise, anorexia, and nausea, or specific signs as jaundice, hepatomegaly, and ascites. While the 35% were asymptomatic and were diagnosed during routine health survey. 10% of cases were diagnosed also by diabetes mellitus.
The oral mucosal signs and symptoms were generally more frequent among HCV compared to healthy controls, while no specific pharyngeal findings were observed in both groups. The frequency of oral findings was statistically significant higher in HCV patients regarding xerostomia (40%), altered taste (24%) and oral lichen planus (20%) [Figure 1]a. However, difference in prevalence of atrophic tongue (18%) [Figure 1]b, oral pigmentation (14%) and pallor (10%) was insignificant between both groups [Table 2]. The presence of HCV was significantly associated with increased odds of xerostomia (P = 0.028, OR=4.3), oral pigmentations (P = 0.013, OR=12.6) and atrophic tongue (P = 0.039, OR=7.8). While other predictors had no significant effects on any of oral findings including the effects of age, sex, duration of hepatitis and even diabetes mellitus. A binomial logistic regression was performed to ascertain the effects of age, sex, diabetes mellitus and different oral diseases on the likelihood of hepatitis occurrence. The logistic regression model was statistically significant, χ2 (12) = 88.17, P < 0.001. The model explained 78.1% (Nagelkerke R2) of the variance in hepatitis. Of the studied predictors, only the decrease of age was significantly associated with decreased odds of hepatitis (P < 0.001) [Table 3] and [Table 4].{Figure 1} {Table 2} {Table 3} {Table 4}
Discussion
Although Hepatitis C is an epidemic disease in Egypt that reached more than 4.6% in adults and caused of 7.6% of the country mortality[4],[21] and only to the author’s knowledge only one published study had evaluated the effect of HCV on oral cavity in Egyptian population[17] and HCV had different six genotypes and the most common genotype in Egypt is type 4 which may reflect different oral manifestations than other genotypes.[22] The literature on correlation between HCV genotypes and different extrahepatic manifestations is still controversial.[23]
The present study revealed significantly higher prevalence of oral and mucosal findings in HCV infected patients (83.33%) compared to (16.67%) in healthy controls. Similar results were generally reported in other reviewed studies[6],[8] and among other populations.[14]
Our results were in contrast to other studies which reported no association between hepatitis C virus infection and oral conditions, as well as insignificant differences between the case and control groups particularly in regional areas with a low prevalence of this infection as in the north of Iran.[11],[24] Interestingly the only similar published study in Banha, Egypt had reported no significant differences between the prevalence of any oral manifestations in HCV patients and control groups except for oral pigmentation[17] Other studies reported a significant correlation between HCV and different oral lesions.,[6],[10] this variations in results of different research could be related to differences in socioeconomic characteristics of these population samples and to different viral genotypes.
The current study reported that the mean age of the cases was significantly higher than that of the control group. Same were reported in previous studies on age specific prevalence rate of HCV indicated high incidence with age.[25],[26] Other study reported that the advancement of age hepatic patients are more liable to have extrahepatic manifestations.[24] This may be due to impaired immunity in older age, reduced mitochondrial capacity and hepatic flow.[25],[26]
Oral Lichen Planus (OLP) was diagnosed in 20% of HCV infected patients in this study according to updated clinical criteria of OLP diagnosis and with histological analysis if needed.[27] However, no OLP lesions were observed in healthy (control) group which was in agreement with other published studies worldwide.[8] Furthermore the reported prevalence of OLP in chronic HCV patients ranged from 1.5% in North America and ranged reached 35% in both Japan and Egypt.[28] Significant association of HCV infection with OLP in the Middle East was reported (OR = 6.01, 95% CI: 1.47–24.53).[29]
The pathogenetic link between OLP and HCV is still under investigation.[30]It was assumed that this link may be a result of HCV replication in the oral mucosa causing a cytotoxic effect on epithelial cells and this may induce lichen planus occurrence.[30] Other studies had reported that the OLP association to HCV may have a regional correlation as it is more reported in specific countries as those of Mediterranean and Southeast Asia.[31] Significantly, abnormal immune reaction to virus especially an excessive TNF-α response was found to characterize HCV-infected patients who developed extra-hepatic manifestation.[32]
Xerostomia was found in the current study in 40%, 12% in study and control groups respectively, with statistically significant difference between the two groups (P = 0.001), which was consistent with other published studies which reported variable incidence of xerostomia in HCV patients.[28] But was in contrast to the Egyptian case-control study which reported 27% of cases with xerostomia compared to 52% in control[17] probably due to improper control of confounding factors in their sample.
The higher incidence of xerostomia in HCV infected patients may be attributed to evasion of HCV to salivary glands causing both sialadenitis and Sjogren like Syndrome (SS).[33] Previous study by Haddad et al. reported that 57% of chronic HCV patients revealed a histological change of Sjogren like Syndrome in salivary of glands.[34] Deficiency in salivary flow may be contributed to various other oral manifestations as candidiasis, difficulty in chewing and talking, dental caries and altered taste.[35]
Atrophic tongue was reported 18% in HCV group and 4% in clinically healthy group with a significant difference (P = 0.025). Previous studies reported the presence of atrophic tongue in HCV cases.[14],[36] This finding may be contributed to prolonged xerostomia in HCV patients that have been reported in previous studies.[37]
Altered taste were recorded in our study in 24% in study group and 4% in clinically healthy group with a statistically significant difference (P = 0.004), this finding may be contributed to the diminished salivary flow that were recorded in hepatitis c group and discussed before, and same findings recorded by other several studies[7],[38]and confirmed by regression analysis [Table 3].
Other associated oral conditions seen in our study, which could be related to symptoms and signs related to pancytopenia, such as jaundice (8%) and pallor (10%) in HCV group and they were statistically significant different from clinically healthy group. The previous results were accordance withs results of previous studies.[13],[24] Hepatitis-associated aplastic anemia (HAA) has been reported which may occur within 6 months of hepatitis C viral infection, as HCV affect levels of serum alanine aminotransferase causing its increase up to five times higher than normal levels.[39] Also, severe marrow aplasia could be induced by viruses as hepatitis viruses (hepatitis B virus and hepatitis C), this may explain the cause of jaundice and pallor findings in our study.[40]
Other less frequent associated oral conditions were reported as candida and fissured tongue and they revealed unsignificant difference between both groups. Similar results were reported in previous study.[6],[30]
Other studies revealed great correlation that exist between the increased incidence of diabetes in patients with chronic liver disease that may be associated with significant changes in the oral cavity such as stomatitis, periodontal disease, cheilitis, candidiasis, oral leukoplakia, and dental caries. Diabetes incidence increased with increased severity of liver disease or as the result of interferon treatment. HCV may act as an independent diabetogenic factor However in our present study we didn’t reveal these findings as we excluded any patents receiving antiviral and those with advanced liver failure.[41]
Although many oral manifestations were recorded in HCV (case) group than healthy (control) group, but within the limitation of the present study the null hypothesis was rejected.
As HCV infection is usually indolent so that patients may present only in late stages of the disease with serious complications like cirrhosis and chronic liver disease, screening of patients with oral findings may help in early diagnosis of the HCV infection in a subset of patients. Early diagnosis, education and awareness of these patients may decrease risk of transmission to others.
The study was limited by single center sampling, however even in this cohort with controlled socioeconomic confounding factors, the oral and mucosal findings published in other worldwide studies were reflected. Furthermore, given the retrospective design of this case–control study, it is impossible to establish whether the HCV exposure occurred earlier to or after the onset of oral findings, thus the causative association couldn’t be confirmed. However, applying therapeutic and preventive measures for HCV patients concerning these findings would be clinically relevant.
A larger sample sized from multiple centers were demanded to avoid limitation of this study.
Conclusion
In a hospital-based sample of Egyptian population; Xerostomia, altered taste and oral lichen planus were significantly frequent with HCV infection in comparison to healthy individuals. While xerostomia, oral pigmentations and atrophic tongue were associated with HCV.
Clinical trial registeration: clinical trials identifier: NCT04812990, https://clinicaltrials.gov/ct2/show/NCT04812990?term=NCT04812990&draw=2&rank=1
Registration number: clinical trials identifier: NCT04812990, https://clinicaltrials.gov/ct2/show/NCT04812990?term=NCT04812990&draw=2&rank=1
Acknowledgment
No acknowledgment
Financial support and sponsorship
The authors declare that they have no funding
Conflicts of Interest
None of the authors has any relevant financial relationships with a commercial interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Authors contribution
the manuscript has been read and approved by all the authors, the requirements for authorship have been met, and that each author believes that the manuscript represents honest work.
Ethical Policy and Institutional Review board statement
The study was conducted in accordance to World Medical Association Declaration of Helsinki. Approval to conduct this study was given by Misr for Science and Technology University Institutional Review Board (MUST-IRB) of research ethics with (Approval number FWA00025577- February 9, 2021).
Patient declaration of consent
Participant’s agreements were taken by signing the informed consent.
Data availability statement
Data is available upon request by Radwa Mohamed Ismail, email: [email protected]
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