Are inflammatory and malnutrition markers associated with metabolic syndrome in patients with sarcoidosis?

SUMMARY OBJECTIVE: The study aimed to investigate the use of Neutrophil/lymphocyte ratio, C-reactive protein/albumin ratio, controlling nutritional status, and prognostic nutritional index immune, inflammatory, and malnutrition markers Metabolic syndrome+ in sarcoidosis patients, as an early-stage marker. METHOD: This is a single-center and cross-sectional study that determines the association of Metabolic syndrome in patients with sarcoidosis. Patients were evaluated based on the National Cholesterol Education Program’s Adult Treatment Panel III criteria. Neutrophil/ lymphocyte ratio, C-reactive protein/albumin ratio, controlling nutritional status, and prognostic nutritional index values were simultaneously determined through blood test. RESULTS: A total of 253 patients diagnosed with sarcoidosis were included in this study. Metabolic syndrome– was detected in 37.2% of patients. The prevalence was significantly higher in females (p<0.001). Any degree of malnutrition assessed by controlling nutritional status had higher Metabolic syndrome (p=0.035). The Neutrophil/lymphocyte ratio cutoff value was 2.24, sensitivity was 70.53, specificity was 60.13, and Area Under the Curve value was 0.663 for predicting Metabolic syndrome in sarcoidosis patients. CONCLUSION: Neutrophil/lymphocyte ratio and controlling nutritional status are associated with the Metabolic syndrome+ in sarcoidosis patients. Thus, close monitoring of Neutrophil/lymphocyte ratio and controlling nutritional status increase in terms of Metabolic syndrome and immune malnutrition may be important in sarcoidosis patients.


INTRODUCTION
Sarcoidosis is a chronic systemic granulomatous disease that commonly affects the lungs.In the course of this disease, neurological findings, uveitis, blindness, end-stage pulmonary fibrosis, pulmonary hypertension, arrhythmia, cardiomyopathy, hypercalcemia, and renal failure may develop; approximately one-third of these side effects progresses as a chronic disease 1 .
Metabolic syndrome (MetS) is a heterogeneous disease that develops on the basis of insulin resistance and involves the combination of systemic disorders such as abdominal obesity, glucose intolerance or diabetes mellitus, dyslipidemia, hypertension, and coronary artery disease (CAD) 2 .The neutrophil/ lymphocyte ratio (NLR) is a systemic inflammatory marker that can be easily measured and used in the prognosis of several chronic diseases.
In a recent study by Gülhan et al., the coexistence of MetS and insulin resistance was evaluated in patients with sarcoidosis and was found to be increased 3 .Due to MetS components, the risk of early atherosclerosis and the presence of abdominal obesity are particularly important in terms of cardiovascular complications.Our study investigated the predictive value of NLR in predicting the incidence of MetS and the presence of MetS in sarcoidosis patients.

METHODS
The study was designed as an observational, cross-sectional study.The patients who were consecutively admitted as outpatient to the pulmonary medicine department were enrolled.The study was approved by the Local Ethics Committee.
All 345 patients diagnosed with sarcoidosis were screened cross-sectionally to evaluate MetS association and NLR according to the National Cholesterol Education Program's Adult Treatment Panel III (NCEP-ATP III) criteria.Those who had received or were planning to receive steroid therapy within the past six months, pregnant women, emergency patients, terminal-stage malignancies, and those with active and suspected infectious diseases were excluded from the study.Finally, a total of 253 patients, 94 sarcoidosis with MetS patients and 159 sarcoidosis without MetS patients, were included in the study.
The presence of diabetes mellitus (DM), hypertension (HT), hyperlipidemia (HL), and cardiovascular disease (CVD) was questioned.Based on additional examinations and follow-ups, those who were diagnosed for the first time had DM, HT, HL, and CVD.

Anthropometric measurements
Each patient underwent a physical examination and a detailed medical examination.Anthropometric measurements and blood pressure measurements were noted.Waist circumference was measured with a tape at the level midway between the lower rib margin and the iliac crest.Blood pressure was measured in the sitting position using a mercury sphygmomanometer with the patients' arm at the level of the heart after they had rested for 15 min in the outpatient clinic.
All patients were evaluated for MetS according to the NCEP-ATP III criteria 4 .The presence of at least three of the five factors defined by ATP III for MetS was accepted as a diagnosis of MetS.European criteria (male ≥94 cm; female ≥80 cm) were used for waist circumference measurement.

Statistical analysis
Variables were investigated using analytical and visual methods (Shapiro-Wilk test and histogram) to determine whether or not they are normally distributed.Continuous variables were presented as mean±SD; if the variables are non-normally distributed, they are presented as median and interquartile range (IQR) 25-75%.Categorical variables were depicted as percentages and numbers.Group comparisons were tested using independent sample t-test or the Mann-Whitney U test, according to distribution of the numerical variables; the chi-square test or the Fisher's exact test was used for the categorical variables.The association between MetS (outcome variable: MetS with sarcoidosis presence) and the CAR, PNI, NLR, age, LDL, and HOMA-IR variables was evaluated using the univariable and multivariable logistic regression models.In addition, receiver operating characteristic (ROC) curve analysis was used to determine whether NLR had discriminative ability for MetS.The independent contribution of each variable to the variance of outcome was estimated.In this regard, the relative importance of each predictor in the model was estimated with a partial 2´ value for each predictor.In addition, correlation analysis was performed for PNI, CAR, HOMA-IR, ACE, and NLR.In all statistical analyses, p<0.05 was considered statistically significant.R software version 4.00 (Vienna, Austria) was used for the statistical analysis.

RESULTS
The study population comprised of 253 patients (190 female patients).There was no statistically significant difference between the groups in terms of age, LDL cholesterol, waist circumferences, lymphocyte, insulin, PNI, and ACE.The MetS+ patients had higher neutrophil, CRP, CAR, and NLR than the MetSpatients, other baseline characteristics were described in Table 1.
The relative importance of each predictor in the model was presented in Figure 1A; the important variables such as NLR and HOMA-IR were used to predict the presence of MetS in the sarcoidosis patient.The partial effect plots show the fitted curve on the mean (probability) scale as log-odds (linear predictor) for NLR in Figure 1B.The NLR cutoff value was 2.24, sensitivity was 70.53, specificity was 60.13, and AUC was 0.663 in predicting MetS in sarcoidosis patients.Herein, a negative correlation existed between NLR and PNI in the correlation analysis [R 0.369 (p<0.001)].However, there was no correlation between HOMA-IR and NLR, PNI, and CAR.

DISCUSSION
This study showed that NLR was higher in sarcoidosis patients with MetS.Chuan-Chuan Liu et al. evaluated patients in six groups using anthropometric, biochemical, and hematological measurements in terms of MetS marker (NLR) in a study including 34,013 subjects.NLR was concluded to be a good predictor, and the risk increased as this ratio increased.NLR and increased values of NLR could be used as a prognostic marker for the development of MetS 5 .In another study, Kaya et al. investigated the relationship between NLR and CAD using syntax score (SS) in 649 patients with stable angina pectoris and CAD; they determined that NLR was a measurable  systemic inflammatory marker.In multivariate analysis, NLR was associated with the presence and severity of CAD 6 .
In their studies including 1300 sarcoidosis patients, Güngör et al. investigated the use of NLR as a marker of inflammation in sarcoidosis.It was concluded that NLR could be used as an inflammation marker, and studies with large patient populations were needed for activity and staging in prognosis 7 .
In the report of Balta et al., NLR value was suggested as an independent prognostic factor for CAD, which may be affected by vascular disease-associated MetS, DM, HT, and hypercholesterolemia 8 .In their case-control study, Büyükkaya et al. divided MetS+ patients into three groups (based on their components).MetS+ patients had significantly higher NLR values compared with the control group, and it was observed that the NLR increased with increasing severity (r=0.586,p<0.001) 9 .Similarly, as a result of our study, NLR was statistically significant as predicted by MetS+.In addition, in the study conducted by Bahadır et al, correlation analysis was performed by comparing metabolic and inflammatory markers between the groups, and it was concluded that NLR is not a good marker of inflammation, and leukocyte and hs-CRP values may be more useful biomarkers to indicate inflammation in nondiabetic patients with obesity and MetS 10 .
In our study, 37.15% MetS+ and 6.73 (3.83-10.2) HOMA-IR values were higher in women and were statistically significant (p<0.001).In the study conducted by Cozier et al., the relationship of obesity and weight gain with the incidence of sarcoidosis was evaluated in 59,000 US black women aged between 21 and 69 years; of these, the development of sarcoidosis was reported in 454 patients during a 16-year follow-up period (1995-2011).The incidence of sarcoidosis increased with increasing body mass index and weight gain 11 .
In the study conducted by Moon et al., patients with elevated CAR and DM were at higher risk of all-cause mortality compared with those without elevated CAR and DM 12 .Similarly, significant results were achieved with CAR and NLR values in predicting inflammation in MetS+ patients (p<0.001).

Gvozdenovic et al. conducted a case-control study with 184
patients and evaluated the effect of high body mass index (BMI) on patient-reported results in sarcoidosis patients and healthy individuals, and the highest risk (more than three times) was detected in obese women 13 .In this study, MetS+ was more common in women and was statistically significant (p<0.001).In the recently published review, the importance of inflammatory parameters was stated, but malnutrition was left out 14 .According to the results of our research, sarcoidosis patients may need to have their inflammation and malnutrition assessed.

Limitations
This study has some limitations.Being a single-center study and its observational nature is one of the limitations of our study.Our findings should be confirmed in prospective and largescale studies involving other inflammatory biomarkers to clarify the exact mechanistic role of NLR in sarcoidosis with MetS+.

CONCLUSIONS
In addition to classical parameters, NLR can be used in sarcoidosis patients to predict MetS+.The use of NLR, a strong inflammation marker, may be considered for the closer follow-up needed in patients with MetS+ sarcoidosis.Sarcoidosis patients should be followed up closely in terms of possible comorbidities through separate evaluation in terms of MetS components in their long-term follow-up.

Figure 1 .
Figure 1.(A) Relative importance of each variable in the multivariable model for predict presence of metabolic syndrome in sarcoidosis.(B) Partial effect plot of neutrophil/lymphocyte ratio for predicting presence of metabolic syndrome+.PNI: prognostic nutritional index; age: years; CAR: C-reactive protein/albumin ratio; LDL: low density lipoprotein; HOMA-IR: homeostatic model assessment-insulin resistance; NLR: neutrophil/lymphocyte ratio.

Table 1 .
Baseline demographic and clinical variables.

Table 2 .
Multivariable logistic regression for predict Metabolic syndrome presence in sarcoidosis.