Does oral isotretinoin treatment increase the risk of atherosclerosis in acne vulgaris patients? The effect of oral isotretinoin on plasma vitamin B12, folic acid, homocysteine, lectin-like low-density lipoprotein receptor 1 (LOX-1) and oxidized low-density lipoprotein (OX-LDL) levels

OBJECTIVE: The aim of this study was to determine the effect of systemic isotretinoin, which is frequently used in the treatment of moderate and severe acne vulgaris, on atherosclerosis by parameters such as B12, folic acid, homocysteine, ox-LDL, LOX-1, triglycerides, total cholesterol, HDL, LDL and VLDL that play a role in the pathogenesis of atherosclerosis. MATERIALS and METHODS: 64 adult female and 17 adult male patient who applied to Manisa Celal Bayar University dermatology outpatient clinic between May 2022- February 2023, with moderate to severe acne and were given oral isotretinoin treatment were included in this study. Each patient was informed about the study and their verbal and written consent was obtained. Patients' age, gender, body mass index, smoking, age of onset of the disease, acne severity, menstrual pattern, familial acne history, co-morbidities and non-acne diseases in the family were questioned. Patients were given oral isotretinoin 0.5 mg/kg per day at the beginning of the treatment. Venous blood samples were taken from patients at the beginning, 1st and 3rd months of treatment. Plasma homocysteine, serum B12, folic acid and OxLDL, LOX-1 levels were analyzed. Lipid levels (Triglycerides, total cholesterol, HDL, LDL, and LDL) routinely measured in the isotretinoin treatment protocol were also recorded. SPSS 25.0 program was used for statistical evaluation. RESULTS: Of the 81 patients who used oral isotretinoin with the diagnosis of acne vulgaris, 13 in the first control and 9 in the second control were out of follow-up, 1 patient did not come to the first control but came to the second control, and a total of 60 patients completed the study. Of the 60 patients, 81.7% (n=49) were female and 18.3% (n=11) were male. The ages of the patients ranged from 18 to 39 years (mean 21.93 ± 3.3); The age of onset of acne ranged from 12 to 39 years (mean 17.38 ± 4.10). The mean body mass index was 22.25± 3.7 (range 16.08-32.81). While 10 (16.7%) of the patients were active smokers, 45 (75%) patients stated that they did not smoke, and 5 (8.3%) patients stated that they quit smoking. While 9 (18.4%) of the female patients had menstrual irregularities, 40 (81.6%) had regular menstruation. Of the 60 patients, 53 (88.3%) did not have co-morbidities, while 7 (11.7%) patients had co-morbidities. These included allergic rhinitis(n=1), asthma(n=1), hypothyroidism(n=1), PCOS(n=4). While the number of people with acne vulgaris disease in the family was 24 (40%), 36 (60%) patients did not have acne vulgaris disease in the family. The number of people with comorbidities in the families of the patients was 21 (35%) and the number of people who did not have any additional diseases was 39 (65%). Additional diseases included kidney failure, diabetes mellitus (DM), hypertension (HT), hyperlipidemia and heart disease. In some families, it was seen that several diseases co-existed. While the severity of acne was moderate in 43 of the patients (71.7%), it was severe in 17 (28.3%) patients. While 45.5% of male patients had moderate acne and 54.5% had severe acne, 77.5% of female patients had moderate acne and 22.5% had severe acne. According to statistical analyses, post-treatment Ox-LDL, triglycerides, total cholesterol, LDL and VLDL levels were significantly higher than the initial values (p<0.001, p<0.01, p<0.001, p<0.001, p<0.01>). Post-treatment levels of LOX-1, folic acid homocysteine and vitamin B12 were statistically insignificant (p>0.05). While Ox-LDL levels were found to increase in men and women according to the presence of co-morbidities and smoking according to the presence of additional diseases and smoking according to the start of treatment, this increase was not statistically significant in smokers (p>0.05) but was statistically significant in all other groups (p<0.001). The relationship between folic acid, vitamin B12 LOX-1 and HDL levels and gender, presence of co-morbidity and smoking was investigated, but the values were not statistically significant (p>0.05). The relationship between homocysteine and gender, presence of co-morbidities and smoking was investigated. While the decrease in homocysteine in women at 3 months was statistically significant (p<0.05), there was no statistically significant finding in the other groups (p>0.05). In both sexes, there was an increase in triglycerides, LDL and VLDL levels compared to baseline levels, and the increase was statistically significant in women (p<0.01). Both sexes had an increase in total cholesterol levels compared to baseline levels and were statistically significant (E, p<0.05; K, p<0.01). The increase in triglyceride and VLDL levels was statistically significant in the non-smoking group (p<0.05). The increase in total cholesterol levels was statistically significant in the smoking and non-smoking groups (p<0.01). The increase in LDL levels was statistically significant in the smoker and non-smoker groups (p=0.05 and p<0.05). According to the additional disease status, an increase in triglycerides, total cholesterol, LDL and VLDL levels in both groups was observed compared to the initial levels. The increase was statistically significant in the group without co-morbidity (p<0.01). In the analysis, a correlation was found between age and initial LOX-1 (p<0.05) and total cholesterol levels (p<0.01), ox-LDL (p=0.01) and triglyceride levels (p=0.001) at month 3 and VLDL levels (p<0.01, p<0.001, p=0.001, respectively). When the correlation between BMI and parameters was evaluated, a correlation was found that was directly proportional to the monthly triglyceride(p<0.05, p<0.01, p<0.05, respectively) and VLDL (p<0.05, p<0.01, p<0.05, respectively), inversely proportional to HDL( p<0.001, p<0.001, p<0.01, respectively). No significant data were found among other parameters (p>0.05). CONCLUSION and RECOMMENDATIONS: While there was a statistically significant increase in Ox-LDL, triglycerides, total cholesterol, LDL and VLDL levels in our study, there was no significant change in vitamin B12, folic acid, homocysteine and LOX-1 and HDL levels. The known atherogenic nature of ox-LDL and lipid profile supports the view that those on isotretinoin therapy have an increased risk of developing atherosclerosis. The increase in ox-LDL, triglycerides, total cholesterol and VLDL levels with increasing age suggests an increased tendency to atherosclerosis in older age. The increase in triglyceride and LDL levels with the increase in BMI, the decrease in HDL levels suggested that the tendency to atherosclerosis increased as the BMI increased. After all; oral isotretinoin use has been found to cause an increase in Ox-LDL, LOX-1 and lipid levels in patients, and it has been suggested that this increase may increase the risk of atherosclerosis. It has been concluded that it would be useful to conduct studies in larger series and with long-term follow-up.