This study was financially supported by personal grants to Jaana Helenius-Hietala from the Finnish Association of Transplant Surgeons and the Paulo Foundation as well as EVO from Helsinki University Central Hospital to this project.
Address reprint requests to Jaana Helenius-Hietala, D.D.S., Institute of Dentistry, University of Helsinki, P.O. Box 41, FI-00014 Helsinki, Finland. Telephone: +358 40 724 7275; FAX: +358 9 191 27286; E-mail: email@example.com
Liver transplantation (LT) was first performed in Scandinavia at the Helsinki University Central Hospital (HUCH) in Finland already 30 years ago. The 5-year survival rates for LT recipients have improved significantly, with recent rates reaching 85%. Despite fewer rejections and better tolerance, immunosuppressive therapy can still cause side effects, among which infections, cardiovascular disease, posttransplant diabetes, kidney insufficiency, and malignancies are the most serious.[1, 2]
Systemic diseases and medications often affect the salivary flow rate and cause hyposalivation, and this may predispose patients to an increased incidence of oral and dental infections such as caries, periodontal disease, and yeast infections.[3, 4] Hyposalivation is diagnosed when unstimulated and stimulated salivary flow rates are significantly reduced: <0.1 mL/minute for unstimulated saliva and <0.7 mL/minute for stimulated saliva. The subjective feeling of dry mouth, xerostomia, is a common complaint among patients taking many drugs daily, but it may not be directly associated with hyposalivation. The consequent oral discomfort due to hyposalivation and xerostomia may lead to difficulties in speaking and swallowing and taste disturbances and finally affect the quality of life.[7-9] These subjective symptoms can be assessed only by the direct questioning of patients.
Recent research into the oral health of patients with liver disease has shown that these patients have a high prevalence of oral infections before transplantation[11-14] and that they also are susceptible to oral diseases and posttransplant infections after transplantation.[15-20] A clinical questionnaire study of chronic kidney disease patients on dialysis was recently conducted, but data on subjective oral symptoms in organ transplant recipients are limited. Therefore, the aim of the present study was to investigate the prevalence and possible risk factors of subjective oral symptoms in a group of LT recipients. The hypothesis was that oral symptoms would differ between LT recipients of different etiology groups and also between LT recipients and controls.
PATIENTS AND METHODS
Eighty-four adult LT recipients (51 men and 33 women) with a median age of 55.1 years (range = 24.6-70.9 years) were recruited for clinical oral and salivary examinations from September 2008 to October 2011 in connection with routine follow-up at the transplant center. The inclusion criteria were as follows: LT was originally performed after the year 2000 at HUCH with a minimum follow-up time of 2 years (252 LT procedures; children were excluded). The median follow-up was 5.7 years (range = 2.0–11.3 years). From that population, 223 LT recipients were alive in 2008 when the recruitment started. All consecutive patients would have been included in this study, but there were some logistical limitations (eg, difficulties with making an appointment for the dental examination on the same day as the follow-up visit, especially for LT recipients traveling from distant locations in the country). Also, the fact that follow-up visits were every 2 to 3 years for LT recipients who had undergone LT more than 3 years ago (164 cases) made it impossible to include all potential LT recipients. Thus, more than half of the eligible LT recipients were included in this study. The 84 patients in this study were categorized as either acute LT recipients (n = 20) or chronic LT recipients (n = 64) according to the etiology of the liver disease.
Control data (n = 252) were obtained from the National Finnish Health 2000 survey, in which 6771 individuals participated in health examinations and home interviews from 2000 to 2001. This large, nationwide survey was designed to obtain information on the most important public health problems in the country, their causes and treatment, and the population's functional capacity and working capacity. Heistaro et al. reported the methodology of this survey in detail. Liver disease was an exclusion criterion for the control subject selection, but individuals with other systemic diseases such as cardiovascular disease and diabetes were not excluded. Three control subjects for each LT recipient (separately for chronic and acute LT recipients) were matched with respect to age, sex, and area of residence. The age matching was performed so that the age of the patient was equal to the age of the control subject in the year 2000.
Data for Systemic Diseases and Medications
LT recipient data for systemic diseases (according to the International Classification of Diseases) and medications (according to the Anatomical Therapeutic Chemical Classification System) were obtained from patient records at the time of the regular follow-up at the transplant center. Data for systemic diseases and medications for the control population were assessed by home interviews as part of the National Finnish Health 2000 survey.
Questionnaire and Oral Examination
The patients filled out a structured questionnaire (see the supporting information) before the clinical oral examination. The questionnaire is a standard form at our clinic that has been used in several other studies.[21, 24] It includes questions about the patient's educational level, working status, and smoking and alcohol use and a self-assessment of oral health. Several questions are designed to assess the possibility of different subjective oral symptoms. Subjects in the control group were not asked the question “Do you have a dry mouth?” (ie, xerostomia), which was included for LT recipients. Instead, the National Finnish Health 2000 survey included the question “Do you have trouble eating dry food without drinking?” (ie, dysphagia), and the same question was also included in the LT recipient questionnaire as well as questions about possible burning mouth syndrome (BMS) and taste disturbances (dysgeusia).
At our center, dental treatment is a prerequisite before an LT candidate can be accepted onto a waiting list. Therefore, all patients with chronic liver disease and those patients with acute liver disease whose medical condition was sufficient underwent a dental evaluation and treatment of infectious dental foci before LT. For this investigation, the LT recipients underwent a new oral examination that included a panoramic radiograph with a clinical investigation of the teeth and the supporting structures. The periodontal status is presented here as a periodontal inflammatory burden index, which is calculated by the addition of the number of periodontal sites indicating moderate periodontitis (periodontal pocket depth ≥ 4 mm but < 6 mm) to the weighed number of periodontal sites indicating advanced periodontitis (periodontal pocket depth ≥ 6 mm). Unstimulated and paraffin-stimulated salivary flow was also measured.
The study has the approval of the HUCH ethics committee (192/13/03/02/2008, August 16, 2008), is in agreement with the Declaration of Helsinki, and is registered in the HUCH database for clinical trials. The LT recipients and also the National Finnish Health 2000 participants were informed about the studies, and they all signed an informed consent form.
Differences between the groups (acute or chronic LT recipients and their matched controls) were calculated via cross-tabulations with the chi-square test, t test, and nonparametric Mann-Whitney U test as appropriate. A binary logistic regression analysis was performed to assess possible risk factors for the subjective oral symptoms. All confidence intervals (CIs) were calculated at the 95% level, and P values < 0.05 were considered significant. The statistical software was PASW 18.0 (IBM Co., Armonk, NY).
The main indication for LT was chronic liver disease: primary sclerosing cholangitis (27.4%), alcoholic cirrhosis (14.3%), primary biliary cirrhosis (PBC; 7.1%), other cirrhosis (including autoimmune hepatitis and viral hepatitis; 10.7%), other liver diseases (eg, Budd-Chiari syndrome; 4.8%), liver tumors (4.8%), or cryptogenic cirrhosis (7.1%). The acute LT recipients included patients with acute or subacute liver disease (23.8%).
The basic characteristics of the study population are given in Table 1. The chronic LT recipients had significantly higher rates of systemic diseases (especially diabetes, cardiovascular disease, and osteoporosis) than their matched controls. The number of medications used daily was significantly higher for the chronic and acute LT recipients versus their controls. Cardiovascular medications were also significantly more frequently used by all LT recipients versus the controls. There were no significant differences in the educational level or the working status between the study groups and the control groups. Working full-time was more common among the controls versus the chronic LT recipients, but there was no significant difference.
Table 1. Basic Characteristics of the 2 Study Groups and Their Controls
Basic oral health and dental behavior data are shown in Table 2. Both chronic LT recipients and acute LT recipients had significantly more caries than their matched controls [1.1 ± 1.5 for chronic LT recipients versus 0.5 ± 1.0 for their controls (P = 0.001) and 0.9 ± 1.1 for acute LT recipients versus 0.5 ± 1.1 for their controls (P = 0.03)]. There was no statistical difference in dental appointments between the LT recipients and the controls even though the LT recipients reported visiting a dentist during the last year more often than the controls. The LT recipients reported their oral health to be good significantly more rarely than the controls in both study groups.
Table 2. Oral Health Status and Behavior of the 2 Study Groups and Their Controls
The chronic LT recipients had significantly less unstimulated saliva secretion than the acute LT recipients (0.34 ± 0.31 versus 0.61 ± 0.49 mL/minute, P = 0.005), as shown in Fig. 1. Reduced unstimulated saliva (≤0.1 mL/minute) was diagnosed in 31.3% of the chronic LT recipients and in 10% of the acute LT recipients. Among the chronic transplant recipients, hyposalivation with unstimulated salivary flow was associated with fewer teeth (17.7 ± 8.2 versus 21.9 ± 8.4, P = 0.047) and more dentures (33.3% versus 12.2%, P = not significant).
The prevalence of subjective oral symptoms is shown in Fig. 2. Xerostomia was common in both chronic LT recipients (48.4%) and acute LT recipients (42.1%). Hyposalivation was associated partly with xerostomia among the chronic LT recipients; 45.5% of the patients diagnosed with hyposalivation in unstimulated saliva reported xerostomia. The chronic LT recipients showed a significantly higher prevalence of dysphagia in comparison with their controls (23.4% versus 11.5%, P = 0.02). BMS was more common among the chronic LT recipients versus their controls (18.8% versus 12%, P = not significant), and dysgeusia was most common in the control population. The acute LT recipients showed the least number of symptoms and even less than the controls. Dysphagia was associated with the number of teeth among the chronic LT recipients (P = 0.05) and among the controls (P = 0.01).
Among the chronic LT recipients, taking ≥8 medications daily increased the risk for xerostomia significantly in comparison with taking ≤4 medications daily [odds ratio (OR) = 4.8, CI = 0.16–0.81, P = 0.005]. Increases in the number of prescribed medications increased xerostomia and dysphagia among the chronic LT recipients, as shown in Fig. 3. The same trend was also seen for xerostomia among the acute LT recipients and for all the symptoms in the control group. In the control population, taking ≥8 medications daily increased the risk for BMS significantly in comparison with taking <4 medications (OR = 4.5, CI = 0.02–0.71, P = 0.04). Increases in the number of prescribed medications (1–4, 5–7, and >8 medications) decreased the objectively measured mean unstimulated salivary flow (0.55, 0.30, and 0.29 mL/minute, respectively) among the chronic LT recipients, but the differences were not significant.
Risk factors for subjective oral symptoms in LT recipients are given in Table 3. Working full-time was associated significantly with a lower prevalence of xerostomia. The risk ratios were 2.63 for alcohol use and 1.22 for the number of medications with respect to xerostomia (P = 0.07). Age was a significant risk factor for BMS, but a longer follow-up time seemed to protect against this. Medications used to treat disorders in the central nervous system (CNS) were a significant risk factor for dysphagia, and removable prostheses increased the risk for dysgeusia.
Table 3. Risk Factors for Oral Side Effects in LT Recipients
NOTE: The following variables were entered into the multivariate binary logistic regression analysis: age, sex, follow-up, diabetes, alcohol use, smoking, number of medications, CNS medications, cardiovascular medications, pulmonary medications, working status, and removable prostheses.
Significant values are bolded.
Number of medications
The purpose of this study was to investigate subjective oral symptoms and associated risk factors in patients receiving immunosuppressive medications. The prevalence of symptoms in 2 LT groups undergoing transplantation because of either chronic liver disease or acute liver failure was compared to the prevalence in control populations.
Differences Between Chronic LT Patients and Acute LT Patients
Chronic LT recipients often use a wide range of medications that may predispose them to oral side effects. The etiology of disease in chronic LT recipients is often immunological in nature, which is known to cause mucosal dryness. One immunological disease can lead to other immunological diseases because several extrahepatic autoimmune diseases, such as thyroid insufficiency (3.6%) and celiac disease (2.4%), and connective tissue diseases (17.2%), such as Sjögren's syndrome, rheumatoid arthritis, sarcoidosis, and gout, have been found in chronic LT recipients. Autoimmune diseases in a patient often overlap, so the cumulative effect on sicca syndrome may be greater than the effect with only 1 autoimmune disease. One example of overlapping in our data was a PBC patient whose liver disease had features of autoimmune hepatitis; this patient also suffered from Sjögren's syndrome and thyroid insufficiency. The high prevalence of diabetes among the chronic LT recipients might also have had an effect on oral symptoms because it is known from previous studies that diabetes is a disease that causes reduced saliva flow and xerostomia.[29, 30]
In general, the acute LT recipients were quite healthy before the sudden acute liver failure that resulted in an urgent need for LT. In contrast to the chronic LT recipients, the acute LT recipients included only 1 patient whose etiology of acute fulminant hepatic failure was suspected to be acute autoimmune hepatitis. Therefore, differences in the medical conditions of the chronic and acute LT recipients may partly explain the observed differences in the oral symptoms and in the oral health status noted between the acute and chronic LT recipients. The small study sample of the acute group, however, probably biased the results, and the explanation for the low prevalence of symptoms among the acute LT recipients remains unclear. Nevertheless, it was an interesting observation that the acute LT recipients reported even fewer oral symptoms than the population controls of this study.
Medications and Oral Symptoms
The subjective feeling of dry mouth (ie, xerostomia) was highly prevalent in both groups of LT recipients: approximately 40% of the acute LT recipients and almost 50% of the chronic LT recipients. Moreover, dysphagia, which often is a result of dry mouth, was reported significantly more frequently among the chronic LT recipients versus the control group but not among the acute LT recipients. The chronic LT recipients had a higher prevalence of all symptoms than the acute LT recipients, who showed symptoms even less frequently than the control population.
It is also known that the greater the number is of drugs taken daily, the greater the effect is on salivary secretion. This was also seen in the present study because as the number of daily medications increased, so did the prevalence of xerostomia and other oral symptoms related to dry mouth both among the LT recipients and among the controls. The increasing number of medications also lowered the objectively measured unstimulated salivary flow rates of the chronic patients. The chronic LT recipients used on average 7 different medications after transplantation. In the long-term, immunosuppressive medications may predispose patients to infections, cardiovascular disease, diabetes, chronic kidney insufficiency, osteoporosis, and malignancies.[1, 2] This was also seen in the present study, in which a significantly higher prevalence of cardiovascular disease, diabetes, and osteoporosis was observed among the chronic LT recipients versus the controls but not among the acute LT recipients.
The explanation for the high prevalence of xerostomia among our patients may be the use of immunosuppressive and other types of xerogenic medications, which may cause hyposalivation. However, it was interesting to see that hyposalivation did not correlate directly with xerostomia because less than half of the chronic LT recipients with diagnosed hyposalivation reported xerostomia. In contrast to this, none of the acute LT recipients showed a correlation between hyposalivation and xerostomia. Dry mouth was mainly felt at night time, and analgesics, antihistamines, and urogenital medications especially seemed to increase the risk for this unpleasant feeling. Cardiovascular medications possibly also accounted for xerostomia because diuretics were found to cause dry mouth in LT candidates in a previous study. Alcohol use also causes dehydration, and we noticed that alcohol use increased the risk for xerostomia but not significantly, and it is noteworthy that the LT recipients used far less alcohol and also smoked less than the population controls.
The association between systemic diseases and salivary dysfunction has been widely discussed in the literature.[32-34] Medications used to treat different CNS disorders (eg, myasthenia gravis, epilepsy, and migraines) as well as medications for depression and insomnia seemed to particularly increase the risk for dysphagia in the present investigation. The pathogenesis of this swallowing disorder may be due to a lack of saliva in the oropharynx caused by CNS and other medications, or it could also be explained by impaired neurological mechanisms of swallowing with an underlying esophageal motility disorder. The low unstimulated salivary flow rates among the chronic LT recipients further emphasize the fact that these patients might have had difficulties in swallowing food and medicines because more than 30% of the chronic LT recipients presented with markedly reduced unstimulated saliva secretions.
Taste disturbances (dysgeusia) are also closely associated with dry mouth, but they are not as common a complaint as xerostomia, which was also seen in this study. Denture wearers might be at risk for dysgeusia because we found removable prostheses to be a risk factor in this regard. Similar findings with respect to dysphagia and dysgeusia were reported by Villa and Abati, but they included cases other than organ transplant patients in their study. In the present study, dysgeusia was not more common among LT recipients versus the control population.
The prevalence of BMS is thought to be less than 10% in the population.[37, 38] In the present study, almost 20% of the chronic LT recipients but only 5% of the acute LT recipients complained about a burning sensation in the oral mucosa, mainly on the side of the tongue. The chronic LT recipients did not show a significantly higher prevalence of BMS in comparison with the controls. A shorter follow-up time seemed to increase the prevalence of BMS, so possibly stronger immunosuppression might have in part been responsible for these symptoms occurring during the earlier stages after transplantation. BMS shows some similarities to PBC; the etiologies for both of these disorders are unknown, and they mainly affect women, who often suffer from sicca syndrome. PBC, however, is associated with several autoimmune diseases and especially with Sjögren's syndrome.[35, 39, 40] Xerostomia and dysphagia are common complaints among PBC patients, and because of the similar pathophysiology in exocrine glands, PBC may be regarded as Sjögren's syndrome of the liver. Thus, as discussed earlier, the autoimmune nature of PBC and other chronic liver diseases may in part explain why the oral symptoms were more prevalent in the chronic LT recipients versus the acute LT recipients.
Subjective Oral Health
The quality of life of LT recipients has been found to be comparable to that of the general population, with a high percentage of LT recipients returning to work after LT. In the present study, approximately 40% of both the chronic and acute LT recipients worked full-time, and this seemed to protect them from the feeling of dry mouth. Although the LT recipients had a slightly lower educational status than the controls, they reported visiting a dentist more often during the last year. Nevertheless, the chronic LT recipients perceived their own oral health to be significantly worse in comparison with the controls. There may be several reasons for this. First, during the course of a chronic disease, patients seem to become aware of the effect of the disease on their oral health. Second, male sex may contribute to a worse oral health outcome because there were more men in the chronic LT group. Third, a lack of teeth and inadequate chewing function may be one explanation because we found a high number of tooth extractions performed before LT in our previous study.[12, 44] Finally and perhaps most importantly, the high prevalence of xerostomia found in this study among LT recipients might explain why the patients felt that their oral health was worse in comparison with the controls.
Clinical Significance of Dry Mouth–Related Symptoms
Normal salivary secretion and composition are fundamental to the well-being of the oral cavity. Oral microbes are flushed away from tooth surfaces more easily and oral mucosa maintains a protective barrier when there is a sufficient amount of saliva in the mouth. Reduced salivary flow is a key risk factor for caries and also is important in other oral infections.
Reduced salivary secretion might be one reason that the chronic LT recipients presented with generally worse oral health than the controls or the acute LT recipients. In addition to an increased incidence of oral infections, reduced salivary secretions may cause oral discomfort. Hyposalivation with eventual dry mouth–related symptoms can be devastating to a patient. Eating and talking become difficult, and wearing dentures can cause pain without the lubricative effect of saliva.
The strength of the present investigation is that it is a part of a prospective oral health study in which self-reported questionnaires have been used in a cross-sectional manner. To the best of our knowledge, the present study is the first to report subjective oral symptoms in this patient group. Furthermore, the controls came from a nationwide, representative sample, and self-reported health questionnaires as such have been shown to be reliable. More than half of the potential subjects scheduled for follow-up at our LT center were included.
There are weaknesses in this study that need to be addressed. The questionnaire was not validated, but it is a standard form that has been used at our clinic in several previous and ongoing studies.[21, 24] We were unable to include data about possible xerostomia in the control group because the national survey did not directly ask about this symptom. However, we did obtain information about dysphagia (ie, difficulties in swallowing dry foods without drinking), and according to the literature, this oral symptom describes the feeling of dry mouth actually better than xerostomia alone. The small study sample of acute LT recipients is another weakness, but the present study's distribution of chronic and acute LT recipients is the same as the distribution in the whole LT population of Finland. Still, the low number of acute LT recipients may have caused bias in the results.
In conclusion, chronic LT recipients showed significantly more dysphagia than their matched controls. According to comparisons of the chronic and acute groups, the chronic transplant recipients presented with a higher prevalence of all subjective oral symptoms, whereas the acute transplant recipients reported even fewer symptoms than the controls. A high number of medications was a significant risk factor for dry mouth–related symptoms in both LT recipients and controls. The chronic transplant recipients presented with lower salivary flow rates than the acute transplant recipients. Hyposalivation among chronic transplant recipients was associated with generally worse oral health. These differences between chronic and acute transplant recipients may be due to differences in medical conditions due to the different etiologies of liver disease.
The authors would like to thank Dr. Miira Vehkalahti (Institute of Dentistry, University of Helsinki, Helsinki, Finland) and Dr. Anna-Lisa Söderholm (Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland) for their kind cooperation in obtaining the control data from the National Finnish Health 2000 survey.