The Relationship of Serum Fibroblast Growth Factor 21 Levels to Intima-Media Thickness in Dyslipidemic Patients

Research Article

J Dis Markers. 2014;1(3): 1012.

The Relationship of Serum Fibroblast Growth Factor 21 Levels to Intima-Media Thickness in Dyslipidemic Patients

Orsag J1*, Karasek D1, Krskova M2, Halenka M1, Vaverkova H1, Gajdova J1, Novotny D3, Lukes J3

1Department of Internal Medicine III - Nephrology, Rheumatology and Endocrinology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Czech Republic

2Computer Centre, Palacky University Olomouc, Czech Republic

3Department of Medical Chemistry and Biochemistry, University Hospital Olomouc, Czech Republic

*Corresponding author: Orsag J, Department of Internal Medicine III - Nephrology, Rheumatology and Endocrinology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Czech Republic

Received: August 15, 2014; Accepted: September 23, 2014; Published: September 29, 2014


Dyslipidemias are very important risk factors for onset of atherosclerosis. Serum fibroblast growth factor 21 (FGF 21) could be a new promising marker to determine the risk of atherosclerosis.However, there is limited information about the relationships of FGF 21 and atherosclerosis in recent literature the aim of this study was to evaluate relationships of serum FGF 21 levels to intimamedia thickness (IMT), as a surrogate marker of subclinical atherosclerosis manifestation, in dyslipidemic patients. We examined 155 individuals divided into 3 groups: dyslipidemic patients with or without metabolic syndrome (MetS+, MetS-) and controls. We found significantly higher serum FGF 21 levels and IMT in MetS+ group than in MetS- group (p<0.05) as well as in controls (p<0.05). In MetS- group and in all dyslipidemic patients (MetS- and MetS+), IMT correlated positively with serum FGF 21 (r=0.486, r=0.573; p<0.01 both). In MetS- group, IMT was independently associated with FGF 21 (p<0.01). We verified independent positive association between IMT and FGF 21 in Caucasian dyslipidemic patients without presence of metabolic syndrome.

Keywords: Fibroblast growth factor 21; Intima-media thickness; Dyslipidemia; Metabolic syndrome


ANOVA: Analysis of variance; ApoA1: Apo lipoprotein A1; ApoB: Apo lipoprotein B; BMI: Body mass index; CCA: Common carotid artery; DBP: Diastolic blood pressure; ELISA: Enzymelinked immunosorbent assay; FGF 21: Fibroblast growth factor 21; GOD-PAP method: Glucose oxidase- peroxidase method; HDL: High density lipoprotein; HDL-C: HDL-cholesterol; Hs-CRP: High sensitivity C reactive protein; IMT: Intima-media thickness; IRMA: Immunoradiometric assay; LDL: Low density lipoprotein; LDL-C: LDL-cholesterol; MetS+: Dyslipidemic patients with metabolic syndrome; MetS-: Dyslipidemic patients without metabolic syndrome; NonHDL-C: NonHDL-cholesterol; SBP: Systolic blood pressure; SPSS: Statistical package for the social sciences; TNF alpha: Tumor necrosis factor alpha; TC: Total cholesterol; TG: Triglycerides


Diseases associated with atherosclerosis as stroke or myocardial infarction play the most important role in mortality and morbidity worldwide, especially in highly developed countries. Beside the classical risk factors, new markers for onset of atherosclerosis are searching. Serum fibroblast growth factor 21 (FGF 21) could be this new promising marker to determine the risk of atherosclerosis.

FGF 21 is a protein predominantly produced by the liver; but it is also expressed in adipocytes and the pancreas [1, 2]. It is widely involved in glucose and lipid metabolism through pleiotropic actions in these tissues and the brain. In mice, fasting leads to increased expression of FGF 21 in the liver where stimulates gluconeogenesis, fatty acid oxidation and ketogenesis, as an adaptive response to fasting and starvation [3]. Administration of recombinant FGF 21 has been shown to confer multiple metabolic benefits on insulin sensitivity, blood glucose, lipid profile and body weight in obese mice and diabetic monkeys [4, 5]. FGF 21 seems to be a promising therapeutic agent for obesity related medical conditions [6]. In contrast with this findings , in human studies, high circulating FGF 21 levels are found in obesity and its related cardiometabolic diseases including the metabolic syndrome, diabetes type 2, non-alcoholic fatty liver disease and coronary artery disease [7,8]. This paradoxical increase of FGF 21 level might be a defensive response of the human body to counteract the metabolic stress, or it maybe caused by resistance to FGF 21 actions, leading to its compensatory up regulation [2, 9]. Serum FGF 21 could be used as potential biomarker for the early detection of these cardiometabolic disorders [10].

The aim of the cross sectional study was to evaluate relationships of serum FGF 21 levels to intima-media thickness of the arteria carotis communis, as a surrogate marker of subclinical atherosclerosis manifestation, in dyslipidemic patients.

Materials and Methods

Study design and subjects

The study cohort included Czech asymptomatic dyslipidemic subjects without lipid modifying therapy and healthy volunteers who underwent carotid IMT measurement in the Lipid Centre of the Department of Internal Medicine III, University Hospital Olomouc, Czech Republic. Medical history was obtained and physical examination performed. All subjects were tested for secondary hyperlipidemia: hypothyroidism, renal or hepatic diseases and nephrotic syndrome. From the study were excluded patients with hypolipidemic therapy in previous 6 weeks, with hormone therapy, with secondary hyperlipidemias, with acute infection or trauma or with acute cardiovascular event in previous 3 month ( without personal history of acute coronary syndrome or myocardial infarction, without elevation of troponin T or ischemic changes on electrocardiogram).Hypertension was defined as a sitting blood pressure of = 120/80 mm Hg, taken as a mean of 3 readings or on regular antihypertensive medications. Dyslipidemia was defined as having one or more of the following criteria: triglycerides (TG) = 1.5 mmol/l, Apo lipoprotein B (apoB) = 1.2 g/l [11]. The value for TG was chosen because small dense LDL particles become common above this level [12], the value for apoB was chosen because it is a level from which cardiovascular risk rapidly increases [13]. Dyslipidemic individuals were divided into two groups: 50 hyperlipidemic patients with presence of metabolic syndrome (MetS+, males/females: 28/22, mean age: 48.3±11.3 years) and 53 hyperlipidemic patients with absence of metabolic syndrome (MetS- , males/females: 25/28, mean age: 41.8±14.5 years). Criteria for identification of MetS were used according to 2001 National Cholesterol Education Program/ ATP III. 50 normolipidemic healthy subjects (males/females: 30/20, mean age: 45.2±16.8 years) served as a control group. The study was reviewed and approved by Ethics Committee of Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc and informed consent was obtained from all participants.

Laboratory analysis

All subjects were assessed after overnight fasting for at least 12 hours. Venous blood samples were obtained and after centrifugation, the serum was used for analysis. Routine serum biochemical parameters were analyzed in the day of blood collection, concentrations of adipokines were measured in the sample aliquots stored at -80 °C, no longer than 6 months. Total cholesterol (TC), TG and high density lipoprotein cholesterol (HDL-C) were determined enzymatically on Modular SWA system (Roche, Basel, Switzerland). HDL-C was measured by direct method without precipitation of apoB containing lipoproteins. Low density lipoprotein cholesterol (LDL-C) levels were calculated using Friedewald formula. NonHDL-cholesterol (nonHDL-C) was calculated as TC - HDL-C. Concentration of apoB and Apo lipoprotein A1 (apoA1) were determined immunoturbidimetrically using Tina-Quant ApoB and ApoA-1 kits (Roche, Basel, Switzerland). Glucose was measured using GOD-PAP method (Roche, Basel, Switzerland). Insulin and C-peptide were determinated by the commercially available kits (Immunotech, Marseille, France) using specific antibodies by the IRMA method. FGF 21 levels were determined using Human FGF 21 ELISA kits (Biovendor Laboratory Medicine Inc., Brno, Czech Republic).

Measurement of carotid IMT

High-resolution B-mode ultrasound (Philips Sonos 5500, 2004) was used to measure the IMT of the common carotid arteries (CCA). Linear array transducers with frequency of 10 MHz was used. The longitudinal image of the CCA was displayed just before the widening of the bulb. When an optimal longitudinal image of the far wall of the CCA in the region of 1 cm proximally from the bulb was obtained, it was frozen on the R wave according to a simultaneous ECG and video tapered. Three video records were made on both CCA. IMT measurements were processed off-line using the software Image- Pro plus (Version 4.0, Media-Cybernetics, Silver Spring, USA). The region under evaluation was the CCA wall 1-2 cm distant proximally from the mentioned border. The average of all mean IMT of three frozen images of both sides was chosen as outcome variable.

Statistical analysis

All analysis was performed with Statistical Package for Social Sciences Version 12.0 (SPSS) (Chicago, IL, USA). Values are expressed as mean ± standard deviation (SD) or median with interquartile range as appropriate. Differences in means between groups were analyzed using ANOVA after adjustment for age and sex. Data that were not normally distributed (FGF 21, hs-CRP, TG, insulin, C-peptide) as determined using Kolmogorov-Smirnov test, were log transformed before analysis. For statistical evaluation of a correlation between individual parameters Pearson correlation analysis was used for variables with normal distribution and an univariate Spearman correlation analysis for variables with skewed distribution. Multiple regression analysis was done for testing of an independent association between dependent and independent variables. Probability values of p<0.05 were considered statistically significant.


The demographic, clinical and biochemical characteristic of the subjects divided in into three groups (healthy controls, dyslipidemic patients with or without presence of metabolic syndrome) are summarized in Table 1. Individuals with MetS (MetS+) had expected unfavorable lipid and lipoprotein profiles (elevated TC, TG, and nonHDL-C, ApoB, and decreased HDL-C and ApoA1) and marked signs of insulin resistance (increased levels of glucose, insulin and C-peptide). FGF 21 concentrations were in this group significantly higher in comparison with both MetS- and controls, whilst differences in FGF 21 levels between MetS- and controls were not significant. Similar results were found in IMT (significantly thicker IMT in MetS+ than in MetS- and in controls, but no difference between MetS- and controls).