病态肥胖患者在接受治疗体重减少后C反应蛋白、肿瘤坏死因子α和白细胞介素-6的水平变化

CRP, but not TNF-α or IL-6, decreases after weight loss in patients with morbid obesity exposed to intensive weight reduction and balneological treatment 病态肥胖患者在接受治疗体重减少后C反应蛋白、肿瘤坏死因子α和白细胞介素-6的水平变化 1 first-author †E-mail:drosc@cm.umk.pl †E-mail:drosc@cm.umk.pl drosc@cm.umk.pl 1 1 2 2 1 1 1 Department of Pathophysiology, Faculty of Pharmacy, Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz, Bydgoszcz PL 85-094, Poland Department of Pathophysiology, Faculty of Pharmacy, Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz, Bydgoszcz PL 85-094, Poland Clinic of Balneology and Physical Medicine, Faculty of Health Science, Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz, Bydgoszcz PL 85-094, Poland Clinic of Balneology and Physical Medicine, Faculty of Health Science, Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz, Bydgoszcz PL 85-094, Poland Objective: 2 The aim of this study was to evaluate the concentrations of C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and the degree of homeostasis model assessment-insulin resistance (HOMA-IR) in patients with morbid obesity exposed to a three-week low-calorie diet and balneotherapy. Methods: 2 The study included 33 patients (25 females and 8 males; mean age 46 years) with body mass index (BMI) values of > 40 kg/m 2 . Evaluations of CRP, IL-6, TNF-α, lipid profile, HOMA-IR, and fasting glucose were carried out before (baseline data) and three weeks after the treatment. The control group consisted of 20 healthy volunteers (15 females and 5 males) with a mean age of 39 years and BMI values of ≤24.9 kg/m 2 . Results: 2 In the blood of patients with morbid obesity we found significantly elevated levels of CRP, TNF-α, triglycerides, HOMA-IR and fasting glucose, but a decreased level of high density lipoprotein (HDL)-cholesterol, compared with the healthy individuals. The treatment resulted in about a 9.4% reduction in body weight from 122.5 to 111.0 kg and a significant decrease in the concentration of CRP, but no change in TNF-α or IL-6. HOMA-IR was significantly reduced. Conclusions: 2 The decrease in CRP level without changes in TNF-α or IL-6 concentrations after the low-calorie diet and balneological treatment, suggests that an essential amount of adipose tissue must be removed before proper adipocyte function is restored. The decrease in HOMA-IR indicates an improvement in insulin sensitivity, which is beneficial in obese patients. 目的 2 评估病态肥胖患者在低热量饮食和浸浴治疗前后，C反应蛋白（CRP）、肿瘤坏死因子α（TNF-α）、白细胞介素-6（IL-6）以及胰岛素抵抗指数（HOMA-IR）的水平变化。 创新点 2 研究炎症反应对病态肥胖的影响。 方法 2 本研究包括33个病例和20个正常对照，对治疗前后的CRP、IL-6、TNF-α、血脂谱、HOMA-IR以及空腹血糖水平进行评估。 结论 2 与对照组相比，低热量饮食和浸浴治疗后，病态肥胖患者的CRP水平显著降低，而TNF-α和IL-6的水平却没有显著变化，这表明脂肪细胞的正常功能恢复之前必须先去除一定量的脂肪组织。HOMA-IR水平的降低说明对胰岛素的敏感性有所提高，这有利于肥胖患者的治疗。 Pro-inflammatory cytokines Tumor necrosis factor-α (TNF-α) Interleukin-6 (IL-6) Morbid obesity C-reactive protein (CRP) Homeostasis model assessment-insulin resistance (HOMA-IR) 促炎性细胞因子 肿瘤坏死因子α 白细胞介素-6 C反应蛋白 病态肥胖症 胰岛素抵抗指数 Introduction 1 Obesity, as a socio-economic issue, is rising in prevalence worldwide. According to the World Health Organization, in 2005 1.6 billion people were overweight and 400 million patients suffered from obesity (Szymocha et al., 2009 2009 ). It is estimated that in North America almost two-thirds of the population are overweight, one-half of whom are obese (Switzer et al., 2013 2013 ). Moreover, in Europe obesity affects 10%–25% of men and 10%–30% of women. Morbid obesity, defined by a body mass index (BMI) of > 40 kg/m 2 , is observed in 3.1% of men and 6.7% of women in the USA (Drenick et al., 1980 1980 ; Switzer et al., 2013 2013 ). Next to genetic factors, environmental factors, especially changes in the lifestyle model towards less physical activity and an excess of high-energy food intake, are considered the main causes of obesity development. Clinical observations and numerous studies have confirmed a higher risk of hypertension, type 2 diabetes, cancers, hyperlipidemia, stroke, asthma, obstructive sleep apnea, and renal failure in association with obesity (Szymocha et al., 2009 2009 ; Switzer et al., 2013 2013 ). Gregor and Hotamisligil ( 2011 2011 ) considered chronic low-grade systemic inflammation a hallmark of obesity. The development of adipose tissue is characterized by enlarging adipocytes and an accumulation of macrophages, resulting in an increase in leptin and a decrease in adiponectin in the blood, and a release into the circulation of cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and chemokines, such as monocyte chemoattractant protein (MCP-1) (Cardillo et al., 2006 2006 ; Gregor and Hotamisligil, 2011 2011 ). The overexpression of TNF-α leads to insulin resistance, reduced lipoprotein lipase activity, and increased lipase activity dependent on hormone (Zahorska-Markiewicz et al., 2000 2000 ). IL-6 stimulates the secretion of glucocorticoids, increasing the affinity of IL-6 receptors on liver cells. This, in turn, increases the production of acute phase proteins, including C-reactive protein (CRP), fibrinogen, plasminogen activator inhibitor type 1 (PAI-1), serum amyloid A, and von Willebrand factor (Gabay, 2006 2006 ). The principal function of CRP is the activation of the complement system and initiation of the elimination of pathogens. CRP inhibits neutrophil adhesion to endothelial cells and reduces the formation of free radicals in neutrophils (Verma et al., 2004 2004 ). The first recommendation in the treatment of overweight or obese patients is lifestyle modification. A low-calorie diet (LCD) is the primary strategy in the treatment of obesity. It is characterized by generating an energy deficit that should be between 500 and 1000 kcal/d (1 kcal=4.1868 kJ). With a negative energy balance, there is possible a weight loss of 0.5 to 1 kg/week (Johansson et al., 2014 2014 ). Specific health benefits after weight reduction were noted: a decrease in blood glucose and serum lipid levels, lower blood pressure, an increase in insulin sensitivity, and a reduction in the use of drugs (Jarosz and Grodowska, 2008 2008 ). Weight loss, regardless of the dietary type, positively influences inflammation markers, decreasing CRP and IL-6 levels (Clifton, 2003 2003 ). Weight loss via diet and physical activity may be supported by balneological treatment (BT), which is a natural therapeutic method involving bathing, drinking, and inhalation of natural mineral water, typically at a spa resort, and also including massage, mud-baths, relaxation, and some exercises in water (Gutenbrunner et al., 2010 2010 ). The minerals absorbed through the skin relieve pain and decrease inflammation, thereby reducing swelling and muscle tension. Thus, obesity is a specific target of balneotherapy, which can have a positive effect (Oláh et al., 2011 2011 ; Hanh et al., 2012 2012 ). A review of the literature shows that there have been few studies analyzing the role of inflammation in morbid obesity. The aim of this study was to evaluate selected markers of inflammation (i.e. CRP, TNF-α, IL-6) and the degree of insulin resistance in patients with morbid obesity given a three-week LCD and BT. Materials and methods 1 The study included 33 patients (25 females aged 28–69 years (mean age 46 years) and 8 males aged 20–56 years (mean age 43 years)) with morbid obesity. The criterion for the patients’ eligibility for the study was a BMI of > 40 kg/m 2 and a lack of symptoms associated with acute or chronic inflammation. The mean duration of obesity was 22.4 years. The patients were under the care of the Clinic of Balneology and Physical Medicine in Ciechocinek, Poland. A medical history interview conducted by a medical specialist revealed information about the general condition of the patients and the occurrence of co-existing diseases: 23 patients suffered from hypertension and 9 had impaired glucose tolerance, but none had overt diabetes. Twenty-eight patients had a family history of dyslipidemia and 12 a family history of diabetes. Among all the patients, 26 had taken hypertension drugs (angiotensin-converting enzyme (ACE) inhibitor drugs) and 4 had undergone anticoagulant therapy. The patients also had received statins and drugs inhibiting gastric acid secretion. In all patients anthropometric parameters were measured including body weight, body shape, and fat content through the measurements of height, weight, and waist circumference. The study involved collection of data at two time points: before treatment (baseline) and three weeks after treatment. The patients were given instructions about the study protocol: during the three-week observation period they should adopt the same lifestyle. The subjects followed a LCD of 1000 kcal/d for 7 d, a very LCD of 400 kcal/d for 4 d, then returned to the LCD until the end of the observation period. The menu was prepared by a professional nutritionist and meals were served at resort restaurants. The daily exercise program included 1 h of brisk walking and 45 min of morning gymnastics. Balneotherapy followed a three-week cycle comprising a mineral water bubble bath at 38 °C for 15 min, mineral water pool exercises at 31 °C for 40 min, and a warm mud bath at 42 °C for 15 min. The evaluations of CRP, TNF-α, IL-6, lipid profile, HOMA-IR, and fasting glucose, and the measurement of anthropometric parameters, were carried out before and 21 d after the treatment. The control group consisted of 20 healthy volunteers (15 females and 5 males) with a mean age of 39 years and a BMI of ≤24.9 kg/m 2 . Table 1 1 shows the clinical data of patients and the control group. Data are expressed as mean±SD or median (Q1; Q3) Parameter Study group ( n =33) Control group ( n =20) P -value  BMI (kg/m 2 ) 44.16±5.55 22.06±1.79 0.0001  WHR 0.93±0.06 0.83±0.05 0.0001  Total-cholesterol (mg/dl) 222.36±36.71 224.40±36.10 0.8446  HDL-cholesterol (mg/dl) 50.00 (42.00; 56.00) 71.00 (57.00; 77.00) 0.0001  LDL-cholesterol (mg/dl) 142.55±36.33 146.68±40.67 0.7065  TG (mg/dl) 119.00 (100.00; 152.00) 71.50 (61.50; 84.00) 0.0001  Body weight (kg) 122.50 (100.90; 137.00) 59.50 (56.50; 65.00) 0.0001  Body fat (%) 51.68±6.70 33.17±4.84 0.0001  Body fat (kg) 61.49±12.40 20.18±3.45 0.0000001  Fasting glucose (mg/dl) 93.00 (88.00; 105.00) 84.00 (79.00; 91.00) 0.0033  CRP (pg/ml) 1916.80 (1025.40; 2070.64) 548.20 (285.04; 1438.68) 0.0004  TNF-α (pg/ml) 11.23±6.48 6.20±5.67 0.0092  IL-6 (pg/ml) 2.91 (2.03; 3.64) 2.91 (2.32; 3.20) 0.8113  HOMA-IR 3.66±2.74 1.39±0.68 0.0050 Venous blood (4.5 ml) for tests of CRP, IL-6, and TNF-α was collected from patients into cooled tubes (Becton Dickinson Vacutainer® System, Plymouth, UK) containing 0.13 mol/L trisodium citrate (the final blood-anticoagulant ratio was 9:1) after 30 min of rest between 7:30 a.m. and 9:30 a.m. after a 12-h overnight fast. The blood samples were immediately mixed and centrifuged at 3000 g at 4 °C for 20 min. The samples were frozen at −20 °C until analysed, but were kept no longer than 6 months. To determine CRP, IL-6, TNF-α, insulin and lipid profiles, 4.5 ml of blood was collected into a tube without anticoagulant after 30 min of rest between 7:30 a.m. and 9:30 a.m. after a 12-h overnight fast.. The sample was centrifuged at 3000 g for 20 min at 4 °C and subjected to further analytical procedures. To evaluate the fasting glucose, blood was sampled into a 4.5-ml tube with sodium fluoride ethylenediaminetetraacetic acid (EDTA). The plasma was centrifuged at 2000 g for 10 min at 4 °C and subjected to further analytical procedures. The body fat measurement was made, and insulin resistance was calculated using the homeostasis model assessment: HOMA-IR=fasting glucose (mmol/L)×fasting insulin (mU/L)/22.5. The concentrations of CRP, IL-6, and TNF-α were assessed by enzyme-linked immuno sorbent assay (ELISA). The concentration of CRP was estimated with human CRP Instant ELISA (Bender MedSystem® GmbH, Vienna, Austria); IL-6 was determined using human IL-6 ELISA, (Bender MedSystem® GmbH, Vienna, Austria). The concentration of TNF-α was assayed using monkey TNF-α ELISA (Bender MedSystem® GmbH, Vienna, Austria). The parameters of the lipid profile, and concentrations of fasting glucose and insulin were recorded following specific tests using the Abbott Clinical Chemistry Analyzer® Architect c8000 (Abbott Diagnostics Europe, Wiesbaden, Germany). Written informed consent was received from each participant before the study. The study was approved by the Bioethics Committee of Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland (No. KB138/2009). Statistical analysis was performed using Statistica 9.0 software (StatStoft®, Cracow, Poland). The Shapiro-Wilk test was used to assess the normality of distributions, which facilitated the use of Student’s t- test; the mean and standard deviation (SD) were determined for each variable. The U-Mann-Whitney rank-sum test was used when the distribution was not normal. Parameters with values deviating from a normal distribution were described by the median, lower quartile (Q1), and upper quartile (Q3). To assess the correlation between the parameters, Spearman’s rank coefficient was applied. P -values of < 0.05 were considered significant. Results 1 Table 1 1 shows the concentrations of CRP, TNF-α, IL-6, and fasting glucose, the lipid profile, level of HOMA-IR, and anthropometric parameters in patients with morbid obesity, compared with those of the control group. There were significantly higher levels of CRP, TNF-α, triglycerides (TG), fasting glucose, and HOMA-IR, and lower HDL cholesterol in the blood of obese subjects, compared with the control group. Moreover, significantly higher BMI, waist-hip ratio (WHR), body weight, and body fat were noted in patients with morbid obesity than in the control group. Table 2 2 shows the concentrations of CRP, TNF-α, and IL-6, HOMA-IR, and anthropometric and selected laboratory parameters in the study group before and after the LCD and BT. A significant decrease in CRP levels was recorded. The mean weight of 122.5 kg in the study group decreased by 11.50 kg (9.4%) after three weeks of the LCD and BT, but the difference was not statistically significant. The treatment resulted in a significant decrease in total-cholesterol, LDL-xcholesterol, HDL-cholesterol, and HOMA-IR. Figs. 1 1 and 2 2 show the significant changes in levels of CRP, IL-6, and TNF-α before and after the treatment. Data are expressed as mean±SD or median (Q1; Q3) Parameter Before treatment ( n =33) After treatment ( n =33) P -value  Body weight (kg) 122.50 (100.90; 137.00) 111.00 (95.90; 131.00) 0.1147  BMI (kg/m 2 ) 44.16±5.55 41.80±5.31 0.0828  WHR 0.93±0.06 0.92±0.06 0.5724  Total-cholesterol (mg/dl) 222.36±36.71 192.12±39.39 0.0019  HDL-cholesterol (mg/dl) 50.00 (42.00; 56.00) 42.00 (36.00; 46.00) 0.0302  LDL-cholesterol (mg/dl) 142.55±36.33 119.85±30.87 0.0081  CRP (pg/ml) 1916.80 (1025.40; 2070.64) 1627.80 (894.10; 1832.70) 0.0106  TNF-α (pg/ml) 11.23±6.48 9.03±10.17 0.8319  IL-6 (pg/ml) 2.91 (2.03; 3.64) 3.49 (2.61; 4.36) 0.1548  HOMA-IR 3.66±2.74 2.71±1.56 0.0050 Table 3 3 demonstrates the correlations between CRP, TNF-α, IL-6 and selected parameters in obese patients before the treatment. There was a significant positive correlation between CRP and BMI and serum TG, a positive correlation between TNF-α and body weight, and a negative correlation between IL-6 levels and HDL-cholesterol. HDL-C: HDL-cholesterol; BW: body weight 2 Parameter 2 CRP 2 TNF-α 2 IL-6 r P r P r P BMI 0.4024 0.0274 0.2834 0.1099 −0.2260 0.2134 HDL-C −0.0457 0.8104 −0.2261 0.2056 −0.3582 0.0441 TG 0.5963 0.0005 0.3058 0.0834 −0.1597 0.3824 BW 0.0512 0.7881 0.3559 0.0420 0.0647 0.7247 Table 4 4 shows correlations between CRP, TNF-α, IL-6 and anthropometric and biochemical parameters in patients with morbid obesity after the treatment. There were significant positive correlations between TNF-α and body fat, BMI, and fasting glucose after the treatment. 2 Parameter 2 CRP 2 TNF-α 2 IL-6 r P r P r P BMI 0.3125 0.0705 0.5339 0.0126 −0.1243 0.5127 Body fat (%) 0.1512 0.5881 0.4975 0.0265 −0.1014 0.6145 Body fat (kg) 0.2456 0.3641 0.5158 0.0198 0.4889 0.6291 Fasting glucose 0.0831 0.7001 0.7053 0.0003 −0.0650 0.7326 Discussion 1 The study demonstrated that, compared with the control group, in the blood of patients with morbid obesity, TNF-α and CRP levels were higher and accompanied by alterations in anthropometric parameters, a higher BMI and WHR, a higher body weight and body fat, and by fluctuations in the lipid profile including higher TG and lower HDL-cholesterol. Moreover, higher fasting glucose and HOMA-IR levels were recorded compared with the control group. CRP is a marker of inflammation, and an increased level of CRP is observed in metabolic diseases such as obesity, type 2 diabetes, and atherosclerosis (Czyżewska et al., 2012 2012 ). The observed increase in CRP levels reported in patients with morbid obesity is consistent with the studies of Hofso et al. ( 2009 2009 ), van Dielen et al. ( 2001 2001 ), and Solá et al. ( 2009 2009 ). In patients with morbid obesity there was a positive correlation between the concentration of CRP and BMI before the BT, which is in line with the results reported by Visser et al. ( 1999 1999 ). These outcomes confirm the presence of low-grade inflammation and tissue damage in those patients. Interestingly, in the current study the CRP level decreased, but no differences in TNF-α or IL-6 concentrations were reported after the LCD and BT. Similar results were obtained by Vázquez et al. ( 2005 2005 ) in patients with morbid obesity four months after bariatric surgery, which indicated that inflammatory pathways, including the TNF-α system and IL-6, remain activated. However, in 22 obese and 20 hypertensive patients subjected to BT with thermal water at 38 °C in 15 sessions (each of 30-min duration), Oláh et al. ( 2011 2011 ) observed a significant decrease in post-treatment CRP levels in a hypertensive group but not in obese subjects. Our results are inconsistent with those reported by Cardillo et al. ( 2006 2006 ) who found no significant improvement in CRP levels of participants following either a low-carbohydrate diet or a conventional low-fat diet for 36 months. Likewise, in 67 severe or morbidly obese patients submitted to a 4-week very low-calorie diet followed by a low-calorie diet for 2 months, Solá et al. ( 2009 2009 ) found no changes in CRP, IL-6, or TNF-α levels after weight reduction (19.6%). These divergent results might be due to the volume of weight reduction, the type of treatment (low-fat, low-carbohydrate, very low-calorie diet, or bariatric surgery), or the duration of the observation period, which tended to differ in each study. TNF-α is considered to be an important factor linking the pathophysiology of obesity with insulin resistance (Cardillo et al., 2006 2006 ). Significantly higher levels of TNF-α in the blood of patients with morbid obesity recorded in the current study are consistent with the results reported by Solá et al. ( 2009 2009 ) in patients with morbid obesity and by Goyal et al. ( 2012 2012 ) in patients with severe obesity (BMI > 30 kg/m 2 ) and type 2 diabetes. Cardillo et al. ( 2006 2006 ) studied 26 low-fat and 27 low-carbohydrate participants with a BMI of > 35 kg/m 2 and found no differences in the concentration of TNF-α after 6 and 36 months of the observation period, independent of the diet regimen. Xydakis et al. ( 2004 2004 ) found no differences in TNF-α concentrations among obese individuals (56 women and 24 men with a BMI of > (38.3±0.7) kg/m 2 ) after 4–6 weeks of weight loss induced by a very low calorie diet. Perhaps the metabolic stress results from a relative starvation effect on the inflammatory response (Vázquez et al., 2005 2005 ; Solá et al., 2009 2009 ). However, Zahorska-Markiewicz et al. ( 2008 2008 ) reported an impact of weight loss on the level of TNF-α in obese women. After three months of treatment based on a 1000 kcal/d diet and increased physical activity, they observed a significant decrease in TNF-α. The current study demonstrated a positive correlation between TNF-α and body weight before BT, and also between TNF-α and body fat, BMI, and fasting plasma glucose after the treatment. The indication of a strong connection between TNF-α and body fat in the obese patients is indirect evidence that this cytokine originates from adipocytes. Visceral adipose tissue is considered a significant source of IL-6 secreted under the influence of TNF-α (Cottam et al., 2004 2004 ). Increased levels of IL-6 were found in the blood of patients with morbid obesity (Solá et al., 2009 2009 ), in patients with type 2 diabetes accompanied by obesity (Goyal et al., 2012 2012 ), and in patients with type 2 diabetes with accompanying albuminuria (Czyżewska et al., 2012 2012 ). An effect of weight loss on serum IL-6 in obese patients undergoing weight reduction was observed by Olszanecka-Glinianowicz et al. ( 2011 2011 ). After three months of therapy they reported a 5% weight reduction and a reduction in IL-6 concentration. Also, after 5 years the concentration of IL-6 was significantly lower than baseline values. However, in the present study, there were no significant differences in IL-6 among patients with morbid obesity, compared with the control group and after the treatment. These divergent results may be linked to polymorphism for IL-6. Gene polymorphism for IL-6 has been observed in impaired hepatic lipid metabolism and insulin resistance (Czyżewska et al., 2012 2012 ). In a study by Bataille and Klein ( 1992 1992 ) there was a positive correlation between IL-6 and BMI, WHR, blood glucose and insulin levels. The present study revealed a significant negative correlation between HDL-cholesterol and IL-6, which confirms the association of IL-6 with dyslipidemia. The mechanism of the effect of IL-6 on the metabolism of carbohydrates and lipids involves the inhibition of the activity of lipoprotein lipase (LPL), stimulating lipolysis, which is accompanied by the accumulation of TG and increased levels of free fatty acids (FFA) (Solá et al., 2009 2009 ). The absence of differences in TNF-α and IL-6 indicates permanent adipocyte abnormalities in morbidly obese patients despite a rapid weight reduction. However, an essential amount of adipose tissue must be lost before proper adipocyte function is restored (Xydakis et al., 2004 2004 ). In the present study, high HOMA-IR in patients with morbid obesity was the evidence of their insulin resistance. However, a short-term LCD and BT improved insulin sensitivity in obese subjects. This was confirmed by the return of HOMA-IR levels to normal values. Conclusions 1 A decrease in CRP levels, but no differences in TNF-α or IL-6 concentrations reported after the LCD and BT, suggests that an essential amount of adipose tissue must be removed before proper adipocyte function is restored. Numerous correlations between TNF-α and CRP and the parameters of carbohydrate and lipid metabolism indicate an important role of inflammation in the pathogenesis of metabolic abnormalities in obesity. Short-term weight reduction decreases the level of HOMA-IR, indicating an improvement in insulin sensitivity, which is beneficial in obese patients. 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The effect of weight loss on serum concentrations of FAS and tumour necrosis factor α in obese women Compliance with ethics guidelines Danuta ROŚĆ, Przemysław ADAMCZYK, Joanna BOINSKA, Robert SZAFKOWSKI, Irena PONIKOWSKA, Katarzyna STANKOWSKA, Barbara GÓRALCZYK, and Barbara RUSZKOWSKA-CIASTEK declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from all patients for being included in the study. Additional informed consent was obtained from all patients for whom identifying information is included in this article. 10.1631/jzus.B1400219 Project supported by the Nicolaus Copernicus University, Collegium Medicum in Bydgoszcz, Poland 2014-08-08 2015-04-09 2015-03-17 2022-01-05 Copyright © Zhejiang University and Springer-Verlag Berlin Heidelberg 2015 2015 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 05 16