The etiopathogenesis of lichen planus (LP) is due to interactions between genetic, environmental, and lifestyle factors 1. LP is probably due to multifactorial causes, sometimes induced by drugs, often idiopathic and with immune-mediated causes involving T cells in particular. The immunologic basis for the disease has been supported by many immunohistochemical and clinical studies 2.
The exact etiology of PL is still unknown and may be caused by cell-mediated immunological response to basal keratinocytes that express altered self-antigen on their surface 3.
Metabolic syndrome is a group of related risk factors for atherosclerosis and diabetes. These factors include dysglycemia, hypertension, high triglyceride (TG) levels, low high-density lipoprotein cholesterol (HDL-C), increased total cholesterol (TC) levels, and obesity (particularly central adiposity) 4. LP and metabolic syndrome share the release of cytokines such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-4, IL-6, IL-10, which are involved in the pathogenesis of LP as well as metabolic syndrome 5.
High-sensitivity C-reactive protein (Hs-CRP) is a nonspecific inflammatory cytokine that increases inflammatory cell infiltration, augmenting oxidative stress, impairing endothelial function as well as decreasing nitric oxide production and accelerates the formation and disruption of atherosclerotic plaque. A significant relation between Hs-CRP/adiponecin ratio and increased carotid intima-media thickness was found, indicating that Hs-CRP/adiponectin ratio is a good predicator for the assessment of risks of atherosclerosis 6.
Pearson et al. 7 suggested that increased Hs-CRP level can be used to represent a risk for cardiovascular disease (CVD). The synthesis of CRP in the hepatocytes is regulated by proinflammatory cytokines like IL-1, IL-6, and TNF 8, which have been linked with LP 9. The raised Hs-CRP level indicates the presence of chronic inflammation which may explain the CVD 10.
The aim of this work was to assess the risk of atherosclerosis in LP patients and its association with dyslipidemia, metabolic syndrome, Hs-CRP/adiponectin ratio, ECG changes, and atherosclerotic cardiovascular disease (ASCVD) risk estimator.
Patients and methods
A total of 40 patients with different clinical types of LP were included in this study with 40 age-matched and sex-matched controls with no dermatological or systemic diseases including patients with renal insufficiency, hepatic insufficiency, patients with a history of CVD, cerebrovascular disease or connective tissue disease, and presence of epithelial dysplasia. Patients on systemic treatment, such as steroid, immune-suppressive treatment, retinoids, or antiplatelet drugs, have been excluded as well. They were randomly selected from The Dermatology Outpatient Clinic, Benha University Hospital during the period from January 2016 to June 2016. Written consents were taken from all patients and controls. This study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practices. The study was approved by the Research Ethics Committee of Benha Faculty of Medicine, Benha University, Egypt, on December 2015. Diagnosis of LP was based on clinical findings.
Patients were excluded if they had any other dermatological diseases, under systemic treatment for LP, aged less than 16 years, or had liver or renal diseases.
General examination was done for all patients and controls to measure height, weight, and waist circumference (WC), calculating the BMI. BMI=weight (kg)/height (m2). Blood pressure (BP) was estimated for all participants. Dermatological examination was done to determine the sites and extent (generalized or localized) of disease.
A volume of 5 ml peripheral venous blood samples were withdrawn from patients and controls. Samples were collected into separator tubes. After clot formation, centrifugation was done and sera were separated and stored at −20°C until analysis.
Hs-CRP and adiponectin were detected quantitatively by enzyme-linked immunosorbent assay (ELISA) method. Hs-CRP/adiponectin ratio was estimated using a calculator. Hs-CRP ELISA kit was provided by Diagnostic Automation/Cortez Diagnostic Inc. (Calabasas, California, USA). Lipid profile [TC, TGs, HDL-C and low-density lipoprotein cholesterol (LDL-C)] and fasting blood sugar (FBS) were measured using Spinreact kit provided by Spinreact Company (Ctra, Santa Coloma, Spain). Adiponectin ELISA kit was provided by Pelobiotech GmbH (Planegg, Germany).
In 2014, The New International Diabetes Federation defined the metabolic syndrome as central obesity (defined as WC ≥94 cm for men and ≥80 cm for women) with any two of the following 11:
- Increased TG: greater than 150 mg/dl (1.7 mmol/l) or specific treatment for this lipid abnormality.
- Decreased HDL-C: less than 40 mg/dl (1.03 mmol/l) in men, less than 50 mg/dl (1.29 mmol/l) in women, or specific treatment for this lipid abnormality.
- Raised BP: systolic blood pressure (SBP) greater than 130 or diastolic BP greater than 85 mmHg, or treatment of previously diagnosed hypertension.
- Raised fasting blood glucose: greater than 100 mg/dl (5.6 mmol/l) or previously diagnosed type 2 diabetes.
Atherosclerotic cardiovascular disease risk estimator
ASCVD risk estimator is an application that predicts 10 years risk for a first ASCVD event. It is approved by the American Cardiology Center/American Heart Association (ACC/AHA) in 2013 as a guideline for the assessment of cardiovascular risks. The ASCVD risk is estimated by data collected from patients including age, sex, race, TC, HDL-C, SBP, BP-lowering medication use, diabetes status, and smoking status. All these data are presented to a program that calculate the risk of atherosclerosis 12.
ECG analysis was performed for all participants using the dedicated ECG Caliber Software (Schiller Cardiovit AT-2, Baar, Switzerland). P-wave duration was defined as the time measured from the onset to the end of the P-wave deflection. The onset of the P-wave was considered as the junction between the isoelectric line and first visible upward or downward slope of the trace. The return of the trace to the isoelectric line was considered to be the end of the P-wave. P-wave dispersion was defined as the difference between maximum and minimum P-wave durations occurring in any of the 12 leads 13.
The data were recorded on an ‘investigation report form’ and were tabulated, coded, and then analyzed using the computer program SPSS (Statistical Package for the Social Sciences; SPSS Inc., Chicago, Illinois, USA) version 22 to obtain descriptive statistics which were expressed in the form of mean, ±SD, number, and percentage. In the statistical comparison between the different groups, the significance of difference was tested using one of the following tests:
- Student’s t-test: to compare between mean of two groups of numerical (parametric) data.
- Pearson’s correlation coefficient (r) test: to correlate different parameters.
- χ 2-Test: to perform intergroup comparison of categorical data.
- P values less than or equal to 0.05 were considered statistically significant.
Patients and controls were sex matched; each group included 20 (50%) men and 20 (50%) women. While the range of ages of the patients was from 20 to 50 years with a mean of 38.1±11.8 years, the range of ages of controls was from 21 to 54 years with a mean of 38±9 years. Seventeen (42.5%) patients were smokers, whereas in the control group 11 (27.5%) were smokers. There was no statistically significant difference in all demographic data between patients and controls.
The median duration of LP was 9 months ranging from 2 to 72 months and the disease was localized to extremities in 37 (92.5%) patients and generalized in three (7.5%) patients, with 32 (80%) patients having pruritus, with no significant difference between patients and controls regarding diabetes mellitus and hypertension (Fig. 1).
The mean of WC in patients was 92±12.3 cm, whereas in controls it was 82.63±9 cm and the mean of BMI in patients was 31.41±3.16 kg/m2, whereas in controls it was 27.1±3 kg/m2, with statistically significant increase in patients than in controls in both WC and BMI.
Laboratory results of patients and controls
There was a statistically significant increase in LDL-C and serum cholesterol in patients than in controls, with a significant increase in HDL-C in controls than in patients. There was no statistically significant difference regarding FBS and TG (Table 1).
The mean level of Hs-CRP levels in patients was 4.97±1.6 mg/l, whereas in controls it was 1.01±0.31 mg/l. Serum levels of adiponectin in patients ranged from 6.23 to 12.25 μg/ml with a mean level of 8.04±1.03 μg/ml, whereas in controls it ranged from 9.5 to 28.6 μg/ml with a mean level of 19.1±4.78 μg/ml with a statistically significant increase in patients than in controls in Hs-CRP/adiponectin ratio (Table 1).
According to the New International Diabetes Federation definition, metabolic syndrome was diagnosed in 22 (55%) patients and six (15%) controls, with statistically significant difference between both groups (Fig. 2).
Atherosclerotic cardiovascular disease score
ASCVD score was significantly increased in patients than in controls as the median was 5.65 ranging from 0.3 to 32.9 in patients and was 1.35 ranging from 0.2 to 9.1 in controls (Table 1).
No statistically significant difference was found between patients and controls as regards ECG changes (P-wave dispersion) as it was found in 16 (40%) patients and in 12 (30%) controls (Table 2).
Significant positive correlations were found between Hs-CRP/adiponectin ratio and duration of disease, TC, LDL-C, metabolic syndrome, ASCVD scores, WC, BMI, and distribution of LP lesions. Significant negative correlation was found between Hs-CRP/adiponectin ratio and HDL-C (Table 3).
Nonsignificant correlations were found between Hs-CRP/adiponectin ratio and age, smoking, SBP, DBP, FBS, TG, ECG changes, and pruritus.
Over the last several decades, significant efforts have been made to predict the risk for atherosclerosis in individuals. Early cohort data, from the Framingham Heart Study, identified the major risk factors, including age, sex, tobacco use, SBP, TC, and HDL-C as strong, independent, predictors of atherosclerosis. Since inflammation is believed to have a role in the pathogenesis of cardiovascular events, measurement of markers of inflammation has been proposed as a method to improve the prediction of the risk of these events 14.
As regards lipid profile in this study, there was a statistically significant increase in LDL-C and serum cholesterol in patients than in controls, with also a significant increase in HDL-C in controls than in patients.
In agreement with this study, Saleh et al. 15 and Panchal et al. 10 discovered higher TC, LDL-C, TG levels, and lower HDL-C levels in LP patients than in controls and the study done by Krishnamoorthy et al. 16 noticed higher TC, LDL-C, VLDL-C, and TGs levels and lower HDL-C levels in LP patients.
During the acute phase of inflammation, lipid metabolism disturbances occur in the form of increased serum TG and decreased HDL-C, which normally help to reduce the toxicity of the causative agent and aid in tissue repair. But if the inflammation becomes chronic, the changes in the lipid profile become sustained and increase the accumulation of cholesterol in cells with the formation of lipid foam cells which in turn produce fatty streaks in the arterial walls. This eventually increases the occurrence of atherosclerotic plaques leading to CVD in LP patients 16.
As regards metabolic syndrome, this study found a significant difference between patients and controls. This is in agreement with the studies done by Arias-Santiago et al. 9, Baykal et al. 17, and Saleh et al. 15.
This could be explained by the increase of Th1 inflammatory cytokines, for example, TNF-α, IL-4, IL-6, and IL-10 found in the skin and blood in LP patients due to chronicity of the disease. A possible biological link between LP and metabolic syndrome is the proinflammatory state exhibited in LP which acts as a central driving force for the development of metabolic syndrome 9.
In the current study, there was a significant difference between patients and controls as regards serum levels of Hs-CRP. This is in agreement with the study done by Saleh et al. 15. In contrast to this result, Baykal et al. 17 did not find a significant difference between patients with LP and controls in the serum levels of Hs-CRP.
In the current study, serum levels of adiponectin were significantly lower in patients than controls. In agreement with this result, a study done by Yuan et al. 18 found the same results.
Jung et al. 19 found a role of ASCVD risk estimator in the prediction of atherosclerosis and declared that ASCVD risk estimator had replaced the whole previous methods in estimating the risks of atherosclerosis.
This study found a significant difference between patients and controls as regards ASCVD risk estimator score. This indicates that patients with LP are more susceptible to atherosclerosis than normal individuals.
As there was a significant difference between patients and controls in lipid profile, metabolic syndrome, Hs-CRP/adiponectin ratio, and ASCVD risk estimator score, patients with LP may have an increased risk for atherosclerosis as well as heart diseases than normal individuals. These results are in agreement with Koseoglu et al. 20, who concluded a possible association of LP with subclinical atherosclerotic, and found that carotid intima-media thickness was increased in patients with LP who had no clinical evidence of heart disease.
The results of the present study were also in agreement with Ertem et al. 21, who also concluded that patients with LP are more liable to atherosclerosis, and confirmed that patients with LP have more epicardial adipose tissue, indicating an increased risk for atherosclerosis.
This study did not find a significant difference between patients and controls in their ECG. In contrast to this study, Sahin et al. 22 discovered a significant difference between patients with LP and controls in their ECG and found P-wave dispersion to be more common in patients than in controls, but they did not state any explanation for this. Balta et al. 23 commented on the result of Sahin et al. 22 and stated that there were a lot of cross-sectional studies that demonstrated that participants with hypertension, obesity, diabetes, and coronary artery disease have an increased P-wave dispersion compared with controls. Apart from the above-mentioned diseases, other causes, such as seasonal variation, alcohol intake, and caffeine ingestion have been demonstrated to affect P-wave dispersion; so these changes in the ECG may not be specific for LP and need more clarifications and more studies.
As regards the correlation between Hs-CRP/adiponectin ratio and different parameters, there were significant correlations between Hs-CRP/adiponectin ratios with ASCVD risk estimator scores indicating that Hs-CRP/adiponectin ratio is a good marker for atherosclerosis.
There was a significant correlation between Hs-CRP/adiponectin ratio with the duration of the disease and its distribution, indicating that the more the duration of disease and the more generalized the affection, and the more the risk of atherosclerosis. This is in agreement with Panchal et al. 10 who discovered a significant correlation between Hs-CRP and the duration of LP and they explained that this is due to the chronic inflammation in LP patients with longer duration.
There was a significant correlation between Hs-CRP/adiponectin ratio with WC and BMI. So the obese patients with LP are the ones more susceptible to atherosclerosis. This is in agreement with Guran et al. 24 who discovered a significant correlation between Hs-CRP and BMI in children who are at a high risk of CHD.
There was a significant correlation between Hs-CRP/adiponectin ratio and metabolic syndrome. This is in agreement with Cattafesta et al. 25 who found a significant correlation between Hs-CRP and metabolic syndrome in their patients.
In brief, lipid profile parameters, metabolic syndrome, and Hs-CRP/adiponectin ratio were significantly higher in patients with LP than in controls indicating that patients with LP are more susceptible to atherosclerosis. A significant positive correlation was found between ASCVD score and Hs-CRP/adiponectin ratio, indicating that Hs-CRP/adiponectin ratio is a good marker for atherosclerosis. The positive correlation between duration and distribution of LP affection with Hs-CRP/adiponectin ratio indicates that increased severity of disease is associated with increased risk of atherosclerosis.
Patients with LP are more susceptible to atherosclerosis affection and metabolic disorders than other healthy individuals. Patients with longer duration of LP affection are more susceptible to atherosclerosis than others. Hs-CRP/adiponectin ratio in LP is a good marker for atherosclerosis.
No financial support.
Conflicts of interest
There are no conflicts of interest.
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