LIVER TRANSPLANTATION 20:72–80, 2014
ORIGINAL ARTICLE
Oral Mucosal Health in Liver Transplant Recipients and Controls € nroos,2 Harri Rissanen,4 Jaana Helenius-Hietala,1,2 Hellevi Ruokonen,2 Lisa Gro 1,5,6 4,7,8 Miira M. Vehkalahti, Liisa Suominen, Helena Isoniemi,3 and Jukka H. Meurman1,2 1 Institute of Dentistry, University of Helsinki, Helsinki, Finland; 2Department of Oral and Maxillofacial Diseases and 3Transplantation and Liver Surgery Clinic, Helsinki University Central Hospital, Helsinki, Finland; 4National Institute for Health and Welfare, Helsinki, Finland; 5Department of Community Dentistry, Institute of Dentistry, University of Oulu, Oulu, Finland; 6Department of Oral and Maxillofacial Diseases, Oulu University Hospital, Oulu, Finland; 7Institute of Dentistry, University of Eastern Finland, Kuopio, Finland; and 8 Department of Oral and Maxillofacial Surgery, Kuopio University Hospital, Kuopio, Finland
Immunosuppressive drugs and other medications may predispose patients to oral diseases. Data on oral mucosal health in recipients of liver transplantation (LT) are limited. We, therefore, recruited 84 LT recipients (64 with chronic liver disease and 20 with acute liver failure) for clinical oral examinations in a cross-sectional, case-control study. Their oral health had been clinically examined before transplantation. The prevalence of oral mucosal lesions (OMLs) was assessed in groups with different etiologies of liver disease and in groups with different immunosuppressive medications, and these groups were compared to controls selected from a nationwide survey in Finland (n 5 252). Risk factors for OMLs were evaluated with logistic regression. OMLs were more frequent in LT recipients versus controls (43% versus 15%, P < 0.001), and the use of steroids raised the prevalence to 53%. Drug-induced gingival overgrowth was the single most common type of lesion, and its prevalence was significantly higher for patients using cyclosporine A (CSA; 29%) versus patients using tacrolimus (TAC; 5%, P 5 0.007); the prevalence was even higher with the simultaneous use of calcium channel blockers and CSA (47%) or TAC (8%, P 5 0.002). Lesions with malignant potential such as drug-induced lichenoid reactions, oral lichen planus–like lesions, leukoplakias, and ulcers occurred in 13% of the patients with chronic liver disease and in 6% of the controls. Every third patient with chronic liver disease had reduced salivary flow, and more than half of all patients were positive for Candida; this risk was higher with steroids. In conclusion, the high frequency of OMLs among LT recipients can be explained not only by immunosuppressive drugs but also by other medications. Because dry mouth affects oral health and OMLs may have the potential for malignant transformation, annual oral examinations are indicated. Liver Transpl 20:72-80, 2014. C 2013 AASLD. V Received April 11, 2013; accepted October 11, 2013. Recipients of liver transplantation (LT) may be predisposed to various oral and dental diseases because of permanent immunosuppression. Drug-induced gingival overgrowth (DIGO) is strongly associated with cyclosporine A (CSA), and this risk is further
increased if an organ transplant patient is using nifedipine or other calcium channel blockers (CACHs) and has poor oral hygiene and untreated periodontitis.1,2 Other oral manifestations in LT recipients include fissured tongue, candidiasis, an increased
Abbreviations: AZA, azathioprine; CACH, calcium channel blocker; CI, confidence interval; CNI, calcineurin inhibitor; CSA, cyclosporine A; DIGO, drug-induced gingival overgrowth; LT, liver transplantation; MM, mycophenolate mofetil; mTOR, mammalian target of rapamycin; OLP, oral lichen planus; OML, oral mucosal lesion; OR, odds ratio; SF, salivary flow; TAC, tacrolimus. The authors have no conflicts of interest to declare. This study was financially supported by Helsinki University Central Hospital (grant T1020Y001), the Finnish Gastroenterology Association, the Finnish Dental Society Apollonia, and the Finnish Dental Association. The Health 2000 health examination survey in Finland was partly supported by the Finnish Dental Society Apollonia and the Finnish Dental Association. Address reprint requests to Jaana Helenius-Hietala, D.D.S., Ph.D., Institute of Dentistry, University of Helsinki, P.O. Box 41, Helsinki, Finland 00014. Telephone: 1358 40 724 7275; FAX: 1358 9 191 27519; E-mail: [email protected] DOI 10.1002/lt.23778 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2013 American Association for the Study of Liver Diseases. V
LIVER TRANSPLANTATION, Vol. 20, No. 1, 2014
incidence of viral infections by herpes simplex types 1 and 2 or cytomegalovirus, graft-versus-host disease, and oral cancer.3-8 In addition to immunosuppressants, LT recipients often take several other medications that may contribute to hyposalivation and xerostomia, which can lead to an increased risk for oral infections and also cause subjective dry mouth– related symptoms.3,9 The dental treatment of LT recipients is aimed at preventing infections.6,10 After transplantation, a careful examination of the lips and oral mucosal tissues for possible neoplastic lesions is important.11 Studies on oral side effects in LT recipients are lacking. We, therefore, studied oral mucosal lesions (OMLs) in groups of LT recipients with different etiologies and immunosuppressive medications, and we compared these groups with a control population. We also investigated risk factors associated with OMLs to better understand the special requirements for the dental management of LT recipients.
PATIENTS AND METHODS Patients LT in Finland is centralized at Helsinki University Central Hospital. This observational, cross-sectional study involved 84 adult LT recipients (>18 years old; 51 men and 33 women; median age 5 55.1 years, range 5 24.6-70.9 years). The same cohort of patients was included in our previous study.9 The main indication for LT was chronic liver disease: primary sclerosing cholangitis (27%), alcohol cirrhosis (14%), primary biliary cirrhosis (7%), cryptogenic cirrhosis (7%), other known cirrhosis (11%; including autoimmune hepatitis and viral hepatitis), other liver diseases (5%; including Budd-Chiari syndrome), and liver tumors (5%). Patients with acute and subacute liver disease (24%) were generally healthy before they experienced sudden liver insufficiency. Two patients underwent combination transplantation (liver and kidney), and 3 patients underwent retransplantation. An oral examination is a prerequisite for transplantation in our country, and all of the chronic LT recipients and some of the acute LT recipients had undergone pretransplant clinical oral examinations with necessary dental treatment before they were accepted onto an LT waiting list. The patients were recruited for a new clinical oral examination after transplantation in connection with a protocol medical follow-up examination at the transplant center. Both pretransplant and posttransplant oral health data were available for a subgroup of 71 patients, but oral health before transplantation was investigated somewhat differently. The posttransplant oral examinations were performed between September 2008 and October 2011. The inclusion criteria required LT to have been originally performed between 2000 and 2006 with a minimum follow-up time of 2 years (n 5 252). In that study population, 223 LT recipients were alive in 2008 when the recruitment started. All consecutive patients would
HELENIUS-HIETALA ET AL. 73
have been included in this study except for logistic limitations such as difficulties in scheduling a dental examination for the day of the follow-up visit (especially for an LT recipient living at a distance). Furthermore, the fact that the protocol follow-up visit was every 2 to 3 years for those LT recipients who had undergone LT more than 3 years previously (n 5 164) made it impossible to include all potential LT recipients. More than half of the eligible LT recipients were included, however. The patients were categorized as either acute LT recipients (n 5 20) or chronic LT recipients (n 5 64) in accordance with the etiology of their liver disease. The groups also reflected the different types of immunosuppression therapy. LT recipient data for systemic diseases (according to the World Health Organization International Classification of Diseases) and prescribed daily medications (according to the World Health Organization Anatomical Therapeutic Chemical Classification System) came from patient records at the time of the protocol followup at the transplant center. The type of underlying liver disease in LT recipients was also recorded from medical files. Information regarding dysphagia, smoking, and alcohol use came from either a questionnaire or an interview for LT recipients9 and controls.12 Current smoking and current alcohol use were assessed for any individuals responding that they were currently smoking or using any alcohol. Data on smoking and alcohol use before transplantation among LT recipients were not available.
Control Population Control data (n 5 252) originated from the Health 2000 survey in Finland: from 2000 to 2001, 6335 individuals participated in a clinical oral health examination, and 6986 participated in a home interview.12 This large, nationwide survey provided information on the most important public health problems in the country and their causes and treatment as well as the population’s functional and working capacity; Heistaro13 reported its methodology in detail. Three control subjects were matched to each LT recipient with respect to age, sex, and area of residence. Liver disease was an exclusion criterion for the control population, but individuals with other systemic diseases such as cardiovascular disease and diabetes were not excluded. Data for systemic diseases (diagnosed by an M.D.) and the total number of prescribed daily medications were assessed with home interviews. The assessment for diabetes was complemented by blood sugar levels and also by data from the drug reimbursement registry.
Clinical Oral Examinations in the Study and Control Groups The clinical oral examinations of the patients were performed by 2 hospital dental specialists (H.Ru. and L.G.). The oral examination also included/consisted
74 HELENIUS-HIETALA ET AL.
information about dentures and how well they fit. Each oral examination included a careful clinical visual inspection of the mucosal and gingival tissues of the oral cavity, including the lips, hard and soft palates, floor of the mouth, inner cheeks, tongue, labial sulcus, and gingiva, for any mucosal or gingival pathology. The presence of different OMLs was reported according to a structured protocol. Clinical oral examinations were performed similarly for the control group. The quality assurance for the clinical measurements in the Health 2000 survey included parallel measurements by the field dentists and the reference dentist. The percentage of unanimous diagnoses regarding oral mucous membrane findings was 87, and the j value was 0.47.12 OMLs included DIGO; mucosal hyperplasia (caused by dentures); denture stomatitis (clinical entity: redness of the oral mucosa under a full denture); oral lichen planus (OLP)–like lesions; lichenoid reactions; leukoplakias (which refer to predominantly white lesions of the oral mucosa that cannot be scraped off or characterized as any other definable lesion); erythroplakias; ulcers; and other OMLs such as angular cheilitis, echymoses, petechiae, fistulas, tumorlike structures (eg, fibromas, hemangiomas, and mucoceles), and other inflammatory OMLs. No amalgam tattoos, frictional keratosis, or materia alba was recorded. For LT recipients, tongue lesions were reported separately (atrophic tongue, fissured tongue, hairy tongue, and geographic tongue).
Salivary and Mycological Sampling in the Study Group Measurements of saliva flow and oral fungal cultivation were performed only for LT recipients. Xerostomia refers to a subjective sensation of dry mouth, whereas hyposalivation is objectively measured via salivary flow (SF). Unstimulated and paraffin-stimulated whole saliva was collected from LT recipients for 5 minutes before the oral examination. For unstimulated saliva, each patient was instructed to passively drool saliva into a collection tube while he or she sat quietly in a dental chair with his or her head slightly bent. For stimulated saliva, a piece of paraffin wax was first chewed for 30 seconds, and then the saliva in the mouth was swallowed; after that, the patient drooled saliva into a collection tube while he or she simultaneously chewed on paraffin approximately once per second. This method of saliva collection was documented by Navazesh and Kumar.14 Hyposalivation was diagnosed when unstimulated and stimulated SF rates were significantly reduced.15 Reduced unstimulated and stimulated SF rates here refer to 0.1 and 0.7 mL/ minute, respectively. The presence of Candida was evaluated via direct mucosal swabs from the oral mucosa of LT recipients, and these swabs were taken routinely from all LT recipients according to the study protocol. Samples from suspected candidiasis lesions in the oral cavity
LIVER TRANSPLANTATION, January 2014
(and from denture surfaces when this was deemed necessary) were transferred with sterile cotton-tipped swabs to the Transpocult transport medium. These samples were then immediately transported to the hospital laboratory for analysis.
Ethical Considerations This study was approved by the ethics committee of Helsinki University Central Hospital (192/13/03/02/ 2008, 16.8.2008), is in agreement with the Declaration of Helsinki, and is registered in the Helsinki University Central Hospital database for clinical trials. Permission for the Health 2000 survey was given by the ethics committees of the University Hospital Region of Helsinki and Uusimaa and the National Public Health Institute. The LT recipients and also the Health 2000 participants were informed about the studies, and each signed an informed consent form.
Statistical Analysis Statistical associations were studied with the chisquare test and Fisher’s exact test (2-tailed) for categorical variables and with the Mann-Whitney U test for continuous variables. A multivariate binary logistic regression analysis (backward Wald) allowed the assessment of possible risk factors for the occurrence of any OML. The following independent variables were entered into the model: case/control, age at oral examination, dysphagia, presence of removable dentures, number of teeth, current alcohol use, current smoking, total number of daily medications, and cardiovascular medications (including beta-blockers, diuretics, angiotensin-converting enzyme inhibitors, and CACHs). These variables were chosen because findings in other studies indicated that they might predispose patients to OMLs. All confidence intervals (CIs) were calculated at the 95% level, and P values 0.05 were considered statistically significant. The statistical software was PASW 18.0 (IBM Co., Armonk, NY).
RESULTS The basic characteristics of the LT recipients and the controls are presented in Table 1, and those results overlap with the results of our earlier study.9 Twentyfive percent of all LT recipients had diabetes after LT. Most already had diabetes before LT; only 3 developed posttransplant diabetes. All OMLs were significantly more frequent in LT recipients versus controls (42.9% versus 14.7%, P < 0.001); comparisons between chronic patients, acute patients, and controls are provided in Table 2. DIGO occurred significantly more often in chronic LT patients versus controls (16.1% versus 1.0%, P < 0.001) and in acute LT patients versus controls (20.0% versus 0.0%, P 5 0.003). OMLs with malignant potential (OLP-like lesions, lichenoid reactions, leukoplakias, erythroplakias, and ulcers) were more common in chronic LT recipients versus controls, but the difference was not statistically
LIVER TRANSPLANTATION, Vol. 20, No. 1, 2014
HELENIUS-HIETALA ET AL. 75
TABLE 1. Basic Characteristics of the 2 Study Groups and Controls Chronic LT
Acute LT
Recipients
Controls
(n 5 64)
Recipients
(n 5 192) P Value
Age during follow-up 56.6 (24.6–70.9) 56.5 (30.0–71.0) visit (years)* Women/men (%) 31.2/68.8 31.2/68.8 Alcohol use (%) 37.5 81.8 Smoking (%) 14.1 24.0 Follow-up after LT (years)* 5.7 (2.0–10.6) Systemic diseases (%) Diabetes 29.7 4.7 Osteoporosis 9.4 2.1 Prescribed daily 6.9 6 2.3 1.9 6 2.1 medications (n)† Different medications (%) 87.5 35.4 Cardiovascular‡ Neurological 15.6 20.8 Analgesic 14.3 20.3 Immunosuppression (%) CSA 52 TAC 42 mTOR inhibitor 6 Corticosteroid 29 AZA 16 MM 33
(n 5 20)
Controls (n 5 60) P Value
54.7 (31.0–70.3) 55.0 (31.0–76.0)
ORIGINAL ARTICLE
Oral Mucosal Health in Liver Transplant Recipients and Controls € nroos,2 Harri Rissanen,4 Jaana Helenius-Hietala,1,2 Hellevi Ruokonen,2 Lisa Gro 1,5,6 4,7,8 Miira M. Vehkalahti, Liisa Suominen, Helena Isoniemi,3 and Jukka H. Meurman1,2 1 Institute of Dentistry, University of Helsinki, Helsinki, Finland; 2Department of Oral and Maxillofacial Diseases and 3Transplantation and Liver Surgery Clinic, Helsinki University Central Hospital, Helsinki, Finland; 4National Institute for Health and Welfare, Helsinki, Finland; 5Department of Community Dentistry, Institute of Dentistry, University of Oulu, Oulu, Finland; 6Department of Oral and Maxillofacial Diseases, Oulu University Hospital, Oulu, Finland; 7Institute of Dentistry, University of Eastern Finland, Kuopio, Finland; and 8 Department of Oral and Maxillofacial Surgery, Kuopio University Hospital, Kuopio, Finland
Immunosuppressive drugs and other medications may predispose patients to oral diseases. Data on oral mucosal health in recipients of liver transplantation (LT) are limited. We, therefore, recruited 84 LT recipients (64 with chronic liver disease and 20 with acute liver failure) for clinical oral examinations in a cross-sectional, case-control study. Their oral health had been clinically examined before transplantation. The prevalence of oral mucosal lesions (OMLs) was assessed in groups with different etiologies of liver disease and in groups with different immunosuppressive medications, and these groups were compared to controls selected from a nationwide survey in Finland (n 5 252). Risk factors for OMLs were evaluated with logistic regression. OMLs were more frequent in LT recipients versus controls (43% versus 15%, P < 0.001), and the use of steroids raised the prevalence to 53%. Drug-induced gingival overgrowth was the single most common type of lesion, and its prevalence was significantly higher for patients using cyclosporine A (CSA; 29%) versus patients using tacrolimus (TAC; 5%, P 5 0.007); the prevalence was even higher with the simultaneous use of calcium channel blockers and CSA (47%) or TAC (8%, P 5 0.002). Lesions with malignant potential such as drug-induced lichenoid reactions, oral lichen planus–like lesions, leukoplakias, and ulcers occurred in 13% of the patients with chronic liver disease and in 6% of the controls. Every third patient with chronic liver disease had reduced salivary flow, and more than half of all patients were positive for Candida; this risk was higher with steroids. In conclusion, the high frequency of OMLs among LT recipients can be explained not only by immunosuppressive drugs but also by other medications. Because dry mouth affects oral health and OMLs may have the potential for malignant transformation, annual oral examinations are indicated. Liver Transpl 20:72-80, 2014. C 2013 AASLD. V Received April 11, 2013; accepted October 11, 2013. Recipients of liver transplantation (LT) may be predisposed to various oral and dental diseases because of permanent immunosuppression. Drug-induced gingival overgrowth (DIGO) is strongly associated with cyclosporine A (CSA), and this risk is further
increased if an organ transplant patient is using nifedipine or other calcium channel blockers (CACHs) and has poor oral hygiene and untreated periodontitis.1,2 Other oral manifestations in LT recipients include fissured tongue, candidiasis, an increased
Abbreviations: AZA, azathioprine; CACH, calcium channel blocker; CI, confidence interval; CNI, calcineurin inhibitor; CSA, cyclosporine A; DIGO, drug-induced gingival overgrowth; LT, liver transplantation; MM, mycophenolate mofetil; mTOR, mammalian target of rapamycin; OLP, oral lichen planus; OML, oral mucosal lesion; OR, odds ratio; SF, salivary flow; TAC, tacrolimus. The authors have no conflicts of interest to declare. This study was financially supported by Helsinki University Central Hospital (grant T1020Y001), the Finnish Gastroenterology Association, the Finnish Dental Society Apollonia, and the Finnish Dental Association. The Health 2000 health examination survey in Finland was partly supported by the Finnish Dental Society Apollonia and the Finnish Dental Association. Address reprint requests to Jaana Helenius-Hietala, D.D.S., Ph.D., Institute of Dentistry, University of Helsinki, P.O. Box 41, Helsinki, Finland 00014. Telephone: 1358 40 724 7275; FAX: 1358 9 191 27519; E-mail: [email protected] DOI 10.1002/lt.23778 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2013 American Association for the Study of Liver Diseases. V
LIVER TRANSPLANTATION, Vol. 20, No. 1, 2014
incidence of viral infections by herpes simplex types 1 and 2 or cytomegalovirus, graft-versus-host disease, and oral cancer.3-8 In addition to immunosuppressants, LT recipients often take several other medications that may contribute to hyposalivation and xerostomia, which can lead to an increased risk for oral infections and also cause subjective dry mouth– related symptoms.3,9 The dental treatment of LT recipients is aimed at preventing infections.6,10 After transplantation, a careful examination of the lips and oral mucosal tissues for possible neoplastic lesions is important.11 Studies on oral side effects in LT recipients are lacking. We, therefore, studied oral mucosal lesions (OMLs) in groups of LT recipients with different etiologies and immunosuppressive medications, and we compared these groups with a control population. We also investigated risk factors associated with OMLs to better understand the special requirements for the dental management of LT recipients.
PATIENTS AND METHODS Patients LT in Finland is centralized at Helsinki University Central Hospital. This observational, cross-sectional study involved 84 adult LT recipients (>18 years old; 51 men and 33 women; median age 5 55.1 years, range 5 24.6-70.9 years). The same cohort of patients was included in our previous study.9 The main indication for LT was chronic liver disease: primary sclerosing cholangitis (27%), alcohol cirrhosis (14%), primary biliary cirrhosis (7%), cryptogenic cirrhosis (7%), other known cirrhosis (11%; including autoimmune hepatitis and viral hepatitis), other liver diseases (5%; including Budd-Chiari syndrome), and liver tumors (5%). Patients with acute and subacute liver disease (24%) were generally healthy before they experienced sudden liver insufficiency. Two patients underwent combination transplantation (liver and kidney), and 3 patients underwent retransplantation. An oral examination is a prerequisite for transplantation in our country, and all of the chronic LT recipients and some of the acute LT recipients had undergone pretransplant clinical oral examinations with necessary dental treatment before they were accepted onto an LT waiting list. The patients were recruited for a new clinical oral examination after transplantation in connection with a protocol medical follow-up examination at the transplant center. Both pretransplant and posttransplant oral health data were available for a subgroup of 71 patients, but oral health before transplantation was investigated somewhat differently. The posttransplant oral examinations were performed between September 2008 and October 2011. The inclusion criteria required LT to have been originally performed between 2000 and 2006 with a minimum follow-up time of 2 years (n 5 252). In that study population, 223 LT recipients were alive in 2008 when the recruitment started. All consecutive patients would
HELENIUS-HIETALA ET AL. 73
have been included in this study except for logistic limitations such as difficulties in scheduling a dental examination for the day of the follow-up visit (especially for an LT recipient living at a distance). Furthermore, the fact that the protocol follow-up visit was every 2 to 3 years for those LT recipients who had undergone LT more than 3 years previously (n 5 164) made it impossible to include all potential LT recipients. More than half of the eligible LT recipients were included, however. The patients were categorized as either acute LT recipients (n 5 20) or chronic LT recipients (n 5 64) in accordance with the etiology of their liver disease. The groups also reflected the different types of immunosuppression therapy. LT recipient data for systemic diseases (according to the World Health Organization International Classification of Diseases) and prescribed daily medications (according to the World Health Organization Anatomical Therapeutic Chemical Classification System) came from patient records at the time of the protocol followup at the transplant center. The type of underlying liver disease in LT recipients was also recorded from medical files. Information regarding dysphagia, smoking, and alcohol use came from either a questionnaire or an interview for LT recipients9 and controls.12 Current smoking and current alcohol use were assessed for any individuals responding that they were currently smoking or using any alcohol. Data on smoking and alcohol use before transplantation among LT recipients were not available.
Control Population Control data (n 5 252) originated from the Health 2000 survey in Finland: from 2000 to 2001, 6335 individuals participated in a clinical oral health examination, and 6986 participated in a home interview.12 This large, nationwide survey provided information on the most important public health problems in the country and their causes and treatment as well as the population’s functional and working capacity; Heistaro13 reported its methodology in detail. Three control subjects were matched to each LT recipient with respect to age, sex, and area of residence. Liver disease was an exclusion criterion for the control population, but individuals with other systemic diseases such as cardiovascular disease and diabetes were not excluded. Data for systemic diseases (diagnosed by an M.D.) and the total number of prescribed daily medications were assessed with home interviews. The assessment for diabetes was complemented by blood sugar levels and also by data from the drug reimbursement registry.
Clinical Oral Examinations in the Study and Control Groups The clinical oral examinations of the patients were performed by 2 hospital dental specialists (H.Ru. and L.G.). The oral examination also included/consisted
74 HELENIUS-HIETALA ET AL.
information about dentures and how well they fit. Each oral examination included a careful clinical visual inspection of the mucosal and gingival tissues of the oral cavity, including the lips, hard and soft palates, floor of the mouth, inner cheeks, tongue, labial sulcus, and gingiva, for any mucosal or gingival pathology. The presence of different OMLs was reported according to a structured protocol. Clinical oral examinations were performed similarly for the control group. The quality assurance for the clinical measurements in the Health 2000 survey included parallel measurements by the field dentists and the reference dentist. The percentage of unanimous diagnoses regarding oral mucous membrane findings was 87, and the j value was 0.47.12 OMLs included DIGO; mucosal hyperplasia (caused by dentures); denture stomatitis (clinical entity: redness of the oral mucosa under a full denture); oral lichen planus (OLP)–like lesions; lichenoid reactions; leukoplakias (which refer to predominantly white lesions of the oral mucosa that cannot be scraped off or characterized as any other definable lesion); erythroplakias; ulcers; and other OMLs such as angular cheilitis, echymoses, petechiae, fistulas, tumorlike structures (eg, fibromas, hemangiomas, and mucoceles), and other inflammatory OMLs. No amalgam tattoos, frictional keratosis, or materia alba was recorded. For LT recipients, tongue lesions were reported separately (atrophic tongue, fissured tongue, hairy tongue, and geographic tongue).
Salivary and Mycological Sampling in the Study Group Measurements of saliva flow and oral fungal cultivation were performed only for LT recipients. Xerostomia refers to a subjective sensation of dry mouth, whereas hyposalivation is objectively measured via salivary flow (SF). Unstimulated and paraffin-stimulated whole saliva was collected from LT recipients for 5 minutes before the oral examination. For unstimulated saliva, each patient was instructed to passively drool saliva into a collection tube while he or she sat quietly in a dental chair with his or her head slightly bent. For stimulated saliva, a piece of paraffin wax was first chewed for 30 seconds, and then the saliva in the mouth was swallowed; after that, the patient drooled saliva into a collection tube while he or she simultaneously chewed on paraffin approximately once per second. This method of saliva collection was documented by Navazesh and Kumar.14 Hyposalivation was diagnosed when unstimulated and stimulated SF rates were significantly reduced.15 Reduced unstimulated and stimulated SF rates here refer to 0.1 and 0.7 mL/ minute, respectively. The presence of Candida was evaluated via direct mucosal swabs from the oral mucosa of LT recipients, and these swabs were taken routinely from all LT recipients according to the study protocol. Samples from suspected candidiasis lesions in the oral cavity
LIVER TRANSPLANTATION, January 2014
(and from denture surfaces when this was deemed necessary) were transferred with sterile cotton-tipped swabs to the Transpocult transport medium. These samples were then immediately transported to the hospital laboratory for analysis.
Ethical Considerations This study was approved by the ethics committee of Helsinki University Central Hospital (192/13/03/02/ 2008, 16.8.2008), is in agreement with the Declaration of Helsinki, and is registered in the Helsinki University Central Hospital database for clinical trials. Permission for the Health 2000 survey was given by the ethics committees of the University Hospital Region of Helsinki and Uusimaa and the National Public Health Institute. The LT recipients and also the Health 2000 participants were informed about the studies, and each signed an informed consent form.
Statistical Analysis Statistical associations were studied with the chisquare test and Fisher’s exact test (2-tailed) for categorical variables and with the Mann-Whitney U test for continuous variables. A multivariate binary logistic regression analysis (backward Wald) allowed the assessment of possible risk factors for the occurrence of any OML. The following independent variables were entered into the model: case/control, age at oral examination, dysphagia, presence of removable dentures, number of teeth, current alcohol use, current smoking, total number of daily medications, and cardiovascular medications (including beta-blockers, diuretics, angiotensin-converting enzyme inhibitors, and CACHs). These variables were chosen because findings in other studies indicated that they might predispose patients to OMLs. All confidence intervals (CIs) were calculated at the 95% level, and P values 0.05 were considered statistically significant. The statistical software was PASW 18.0 (IBM Co., Armonk, NY).
RESULTS The basic characteristics of the LT recipients and the controls are presented in Table 1, and those results overlap with the results of our earlier study.9 Twentyfive percent of all LT recipients had diabetes after LT. Most already had diabetes before LT; only 3 developed posttransplant diabetes. All OMLs were significantly more frequent in LT recipients versus controls (42.9% versus 14.7%, P < 0.001); comparisons between chronic patients, acute patients, and controls are provided in Table 2. DIGO occurred significantly more often in chronic LT patients versus controls (16.1% versus 1.0%, P < 0.001) and in acute LT patients versus controls (20.0% versus 0.0%, P 5 0.003). OMLs with malignant potential (OLP-like lesions, lichenoid reactions, leukoplakias, erythroplakias, and ulcers) were more common in chronic LT recipients versus controls, but the difference was not statistically
LIVER TRANSPLANTATION, Vol. 20, No. 1, 2014
HELENIUS-HIETALA ET AL. 75
TABLE 1. Basic Characteristics of the 2 Study Groups and Controls Chronic LT
Acute LT
Recipients
Controls
(n 5 64)
Recipients
(n 5 192) P Value
Age during follow-up 56.6 (24.6–70.9) 56.5 (30.0–71.0) visit (years)* Women/men (%) 31.2/68.8 31.2/68.8 Alcohol use (%) 37.5 81.8 Smoking (%) 14.1 24.0 Follow-up after LT (years)* 5.7 (2.0–10.6) Systemic diseases (%) Diabetes 29.7 4.7 Osteoporosis 9.4 2.1 Prescribed daily 6.9 6 2.3 1.9 6 2.1 medications (n)† Different medications (%) 87.5 35.4 Cardiovascular‡ Neurological 15.6 20.8 Analgesic 14.3 20.3 Immunosuppression (%) CSA 52 TAC 42 mTOR inhibitor 6 Corticosteroid 29 AZA 16 MM 33
(n 5 20)
Controls (n 5 60) P Value
54.7 (31.0–70.3) 55.0 (31.0–76.0)
