Nghiên cứu hội chứng chuyển hóa và nồng độ leptin, IL 1β huyết tương ở bệnh nhân thoái hóa khớp gối nguyên phát tt tiếng anh

.MINISTRY OF EDUCATION AND MINISTRY OF TRAINING DEFENCE VIETNAM MILITARY MEDICAL UNIVERSITY NGUYEN THI THANH MAI METABOLIC SYNDROME, PLASMA LEPTIN AND IL-1β CONCENTRATIONS IN PATIENTS WITH PRIMARY KNEE OSTEOARTHRITIS Speciality : INTERNAL MEDICINE Code : 72 01 07 THE SUMMARY OF THE MEDICAL DOTORAL THESIS HANOI – 2019 THIS DOCTORAL THESIS WAS COMPLETED AT VIETNAM MILITARY MEDICAL UNIVERSITY Scientific Instructors: A/PROF Ph.D Do Trung Quan A/PROF Ph.D Dao Hung Hanh 1st Contradictor: A/PROF Ph.D Nguyen Thanh Thuy 2nd Contradictor: PROF Ph.D Vo Tam 3rd Contradictor: A/PROF Ph.D Doan Van De The doctoral thesis will be reported to The Grading and Examinations Committee hold at Vietnam Military Medical University at 2019 Searching for the dissertation at: - National Library - Vietname Military Medical University’s library INTRODUCTION Osteoarthritis (OA) was the result of interaction between biomechanics and chronic low-stage inflammation Metabolic syndrome (MS) included central obesity, dyslipidemia, impaired fasting glucose, and hypertension in which obesity was the most important The prevalence of MS increased in the OA compared with the non-OA group Obesity was a significant risk factor for knee OA (KOA) through mechanisms of increasing mechanical load and chronic low-stage inflammation Low-stage chronic inflammation associated with adipokines (leptin) interacts with pro-inflammatory cytokines of which interleukin1β (IL-1β) was a key role in maintaining cartilage ulcers, substrate degradation in obesity pathogenesis mechanism caused OA Therefore, the thesis “Metabolic syndrome, plasma leptin and IL-1β concentrations in patients with primary knee osteoarthritis” was conducted with two objectives: To determine the prevalence of metabolic syndrome, its components and the relationship with the stages of primary knee osteoarthritis To determine the relationship of plasma leptin and IL-1β concentrations with some clinical and subclinical features in patients with primary knee osteoarthritis * The scientific significance: Increasing the incidence of MS in the OA, MS and OA were shared the pathogenesis mechanism related to obesity, low-stage chronic inflammatory response and adipokines (leptin) or pro-inflammatory cytokines (IL-1β) * The practical significance: Described the specific value of the prevalence of MS, plasma leptin and IL-1β concentrations in KOA and compared with the control It was recommended to identify a KOA patient with MS accompanying control of two problems simultaneously Leptin should be quantified in patients with KOA who not meet the diagnostic criteria for MS, to determine a group of KOA patients at high risk of MS, for early intervention * New contributions of this doctoral thesis This was the first scientific study in Vietnam on MS, plasma leptin and IL-1β concentrations in patients with primary KOA The prevalence of MS in KOA was 51.7% and its increased when the stage of KOA increased Determination of plasma leptin and IL-1β concentrations of the KOA patients were higher than the control; the correlation between leptin and IL-1β were determined with some metabolic risk factors Determination of the cut-off point of plasma leptin concentrations that predicts a patient with knee osteoarthritis who may suffer from MS * The doctoral thesis arrangement: This thesis contains 125 pages (without references and appendixes): Introduction: 02 pages, Chapter Overview: 35 pages, Chapter Subjects and methods: 28 pages, Chapter Results: 32 pages, Chapter Discussion: 37 pages, Conclusion: 02 pages, Recommendations: 01 page It includes 33 tables, graphs, 16 figures, diagram and 174 references (7 Vietnamese references and 167 English references) CHAPTER 1: OVERVIEW 1.1 Overview of osteoarthritis 1.1.1 Diagnosis of osteoarthritis Diagnosis of OA was based on the ACR 1991 criteria 1.1.2 New views of the pathogenesis of osteoarthritis 1.1.2.1 Low-stage chronic inflammation Adipokines (leptin, resistin ) and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6 ) were related to the common mechanism of MS and OA Hypothesis on the independent role of low-stage chronic systemic related to obesity and MS were caused the onset of OA 1.1.2.2 Pro-inflammation cytokine (IL-1β) IL-1β was a strong pro-inflammatory cytokine, important in the early stages of OA because it was not only increased cartilage catabolism (inhibiting type II collagen and aggrecan synthesis leads to substrate degeneration) but also inhibited cartilage anabolic IL-1β stimulated IL-6 and IL-8 production; contributed to inflammation (localized in synovial or systemic inflammation) Chondrocytes were the main target cells of IL-1β, degenerative chondrocytes were higher sensitive to the effects of IL-1β to 4-fold than normal chondrocytes Only 1% of IL-1β receptors on active cartilage surface can convert chondrocytes into a form of strong catabolism 1.1.2.3 Adipokine (Leptin) Leptin was an energy-regulating hormone, also a proinflammatory factor that caused inflammation and catabolism of chondrocytes Leptin resistance was the action of leptin that failed when leptin concentrations increased There was still controversy about leptin causing degeneration or repair of cartilage Cartilage: Leptin acts on both cartilage anabolism and catabolism Leptin acts on chondrocytes through mechanisms of inflammation and catabolism, producing IL-1β, MMP-9, MMP-13 , contributing to cartilage degradation Leptin caused cell proliferation, increased collagen synthesis, stimulated endothelial calcium, increased bone mineralization, increased growth factor IGF-1 and TGF-β1 (Dumond H.) Bone: Leptin regulated bone growth indirectly through the neural network, inhibiting bone formation Leptin directly enhanced cells that develop cortical bone, collagen synthesis and bone mineralization, stimulating the formation of cartilage 1.2 Metabolic syndrome Metabolic syndrome, whose elements include central obesity, dyslipidemia, impaired fasting glucose, and hypertension, increases the risk of cardiovascular disease and mortality In this study, MS was diagnosed according to IDF criteria 1.3 Relationship between metabolic syndrome and osteoarthritis 1.3.1 Obesity and osteoarthritis Obesity contributed to OA through low-biomechanics and chronic inflammation Adipose tissue produced adipocytokines such as leptin in combination with pro-inflammatory cytokines such as IL-1 derived from macrophages in adipose tissue, causing inflammation of synovial membranes, cartilage degeneration, changes in subchondral bone that caused OA 1.3.2 Glucose, insulin resistance and osteoarthritis Chronic hyperglycemia caused oxidative stress, increased proinflammatory cytokine production, AGEs accumulation in joint tissues, and differentiation of potential stem cells, insulin resistance at local synovial membranes and low-stage chronic inflammation 1.3.3 Lipid and osteoarthritis There were many epidemiological and experimental evidence of dyslipidemia related to OA Lipid deposition in chondrocytes occurred early Another hypothesis was oxidized LDL (oxLDLs), which caused atherosclerosis, promoted inflammation in OA Increasing free fatty acids can cause insulin resistance 1.3.4 Hypertension and osteoarthritis Hypertension caused endothelial dysfunction; reduction of neural dynamics, localized perfusion reduction in peripheral organizations including cartilage, reduction of oxygen and nutrient supply, reduction of metabolism in cartilage In addition, local ischemia led to apoptosis of subcutaneous bone cells and subcortical bone abnormalities 1.4 Recent researches 1.4.1 Metabolic syndrome and osteoarthritis researches According to the data of NHANES III, there were 7714 subjects, the prevalence of MS was 59% in OA group compared with 23% in the non-OA, one person with OA in middle age had a risk of MS increased 5.26-fold 1.4.2 Leptin and osteoarthritis researches Leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) female mice compared with wild-type mice were studied Extreme obesity due to impaired leptin signaling induced alterations in subchondral bone morphology without increasing the incidence of knee OA Systemic inflammatory cytokine levels remained largely unchanged in ob/ob and db/db mice These findings suggest that body fat, in and of itself, may not be a risk factor for joint degeneration, because adiposity in the absence of leptin signaling is insufficient to induce systemic inflammation and knee OA in female mice (Griffin T.M.) 1.4.3 Leptin, metabolic syndrome and osteoarthritis researches Increased leptin levels in both women and men with MS Leptin predicted that MS was independent of obesity Leptin increased in MS, correlated with the number of components of MS and leptin was an important risk factor for KOA in women Insulin resistance was associated with increased KOA in men, increased leptin levels was associated with increased KOA in women 1.4.4 IL-1β and osteoarthritis researches Ning L et al found IL-1β concentrations related to the severity of the disease so it was a marker for the severity of OA Nguyen Ngoc Chau found that plasma IL-1β concentrations in OA patients was higher than the controls CHAPTER 2: SUBJECTS AND METHODS 2.1 Subjects 582 primary KOA patients and 78 healthy control individuals were recruited during 2014 - 2019, at Bachmai hospital 2.1.1 Study group Inclusion criteria: Diagnosed primary KOA based on the ACR 1991 and MS based on the IDF 2005 criteria Exclusion criteria: secondary KOA, patients did not consent 2.1.2 Controls 78 healthy individuals 2.2 Research methods 2.2.1 Study design Prospective, descriptive cross-sectional study 2.2.2 Sampling method Sample size for aim 1: p = 0.59 d = 0.04 ∝ = 0.05 n = 580.8 We selected 582 patients in the KOA group Z2(1-∝/2) × p × (1-p) n= d2 Sample size for aim 2: σ = 0.3 d = 0.05 ∝ = 0.05 n = 138.3 Z2(1-∝/2) × σ2 n= d2 We selected 164 patients in the KOA* and 78 healthy individuals in the controls The KOA* was similar to KOA about age, BMI, gender rate and the prevalence of MS 2.2.3 Quantification of leptin and IL-1β plasma Plasma leptin test by the Human leptin ELISA kit of Sigma; plasma IL-1β test by Human IL-1β ELISA kit of Melsin, using human monoclonal antibodies 2.3 Data processing Using medical statistics softwere: SPSS 20.0 2.4 Research diagram Diagnosis of KOA WC, blood pressure, HDL-C, triglyceride, glucose, HbA1c, insulin … KOA* (n = 164) KOA (n = 582) CONTROLS healthy people (n = 78) Leptin, IL1β To determine the prevalence of MS, its components and the relationship with the stages of primary KOA 2 To determine the relationship of plasma leptin and IL-1β concentrations with some clinical and subclinical features in patients with primary KOA RECOMMENDATION S CHAPTER 3: RESULTS 3.1 Demographic, anthropometric, biochemical and clinical characteristics in knee osteoarthritis group Table 3.1 In 582 KOA patients, women were 86.6%; mean ages were 56.7 ± 8.2 years; mean BMI was 24.0 ± 3.0 kg/m Table 3.6 No statistical differences between the mean ages, BMI, WC, WHR, hypertension, HbA1c, CRP between men and women groups 3.2 The prevalence of metabolic syndrome and the relationship with the stages of primary knee osteoarthritis Table 3.8 The prevalence of MS and its components by sex Total (n = 582) n (%) Women (n = 504) n (%) Men (n = 78) n (%) MS 301 (51.7) 279 (55.4) 22 (28.2) High WC 415 (71.3) 392 (77.8) 23 (29.5) Low HDL-C 314 (54.0) 283 (56.2) 31 (39.7) Hypertension 374 (64.3) 321 (63.7) 53 (67.9) 254 (43.6) 220 (43.7) 34 (43.6) 329 (56.5) 279 (55.4) 50 (64.1) 201 (34.5) 175 (34.7) 26 (33.3) Variables High fasting glucose High triglycerides Obese p women - men OR (95% CI) < 0.001 3.2 (1.9 - 5.3) < 0.001 8.4 (4.9 - 4.2) < 0.05 1.9 (1.2 - 3.2) > 0.05 0.83 (0.5 - 1.4) > 0.05 1.0 (0.6 - 1.6) > 0.05 0.7 (0.4 -1.1) > 0.05 1.1 (0.6 -1.8) The prevalence of MS among KOA was 51.7%, it was statistically higher in women than men, with odds ratio was 3.2 The prevalence of high WC, low HDL-C in women with KOA was significantly higher than in men No statistical differences of the prevalence of 11 Table 3.17 Leptin, IL-1β, IL-1β/leptin in KOA* by obese Variables Obese (n = 59) Non obese (n = 105) (n = 164) Median (Q1 - Q3) Median (Q1 - Q3) Leptin (ng/mL) 13.0 (10.4 - 15.8) 7.9 (4.5 - 11.5) < 0.001 IL-1β (pg/mL) 9.7 (8.8 - 12.1) 10.1 (8.6 - 13.4) > 0.05 IL-1β /leptin 0.8 (0.6 - 1.5) 1.4 (0.9 - 3.3) < 0.001 p KOA*: Leptin concentrations in the obese were higher than in the non-obese; IL-1β were not statistically different IL-1β/leptin ratio in the non-obese was higher than in the obese Table 3.18 Leptin, IL-1β, IL-1β/leptin in KOA* by MS OA with MS (n = 85) Variables OA without MS (n = 79) p (n = 164) Median (Q1 - Q3) Median (Q1 - Q3) Leptin (ng/mL) 11.6 (8.7 - 15.7) 7.7 (3.9 - 11.4) < 0.001 IL-1β (pg/mL) 10.3 (8.9 - 13.5) 9.8 (8.6 - 12.0) > 0.05 IL-1β/leptin 1.0 (0.6 - 1.7) 1.4 (0.8 - 3.4) < 0.01 KOA*: Leptin concentrations in MS group were higher than the non-MS; IL-1β were not statistically different IL-1β/leptin ratio in the KOA without MS was higher than the KOA with MS Table 3.21 Leptin, IL-1β, IL-1β/leptin in controls Variables Tổng Men Women (n = 78) (n = 11) (n = 67) Leptin Median 0.5 0.1 0.5 (ng/mL) Q1 - Q3 0.3 - 0.7 0.03 - 0.2 0.4 - 0.8 IL-1β Median 6.9 6.6 6.9 (pg/mL) Q1 - Q3 6.4 - 7.5 6.3 - 7.5 6.4 - 7.6 Tỉ số Median 13.9 132.1 13.5 p < 0.001 > 0.05 < 0.001 12 IL-1β /leptin Q1 - Q3 9.6 - 24.9 27.2 - 227.5 9.4 - 19.2 Controls: Leptin concentrations in women was significantly higher than in men; IL-1β were not significantly different; IL-1β/leptin ratio in the men was higher than in the women Table 3.22 Leptin, IL-1β, IL-1β/leptin in KOA* and controls KOA* (n = 164) Controls (n = 78) Median (Q1 - Q3) Median (Q1 - Q3) Leptin (ng/mL) 9.5 (5.8 - 14.3) 0.5 (0.3 - 0.7) < 0.001 IL-1β (pg/mL) 10.0 (8.8 - 12.8) 6.9 (6.4 - 7.5) < 0.001 IL-1β/leptin 1.2 (0.7 - 2.2) 13.9 (9.6 - 24.9) < 0.001 Variables p KOA*: Plasma concentrations of leptin and IL-1β were higher, IL-1β/leptin ratio was lower than in the healthy controls Table 3.23 Leptin, IL-1β, IL-1β/leptin in three groups Variables OA with MS OA without MS Controls (n = 85) (n = 79) (n = 78) Leptin Median 11.6 7.7 0.5 (ng/mL) (Q1 - Q3) (8.7 - 15.7) (3.9 - 11.4) (0.3 - 0.7) IL-1β Median 10.3 9.8 6.9 (pg/mL) (Q1 - Q3) (8.9 - 13.5) (8.6 - 12.0) (6.4 - 7.5) IL-1β /leptin Median 1.0 1.4 13.9 (Q1 - Q3) (0.6 – 1.7) (0.8 – 3.4) (9.6 - 24.9) p < 0.001 < 0.001 < 0.001 The concentrations of leptin and IL-1β tended to decrease in three groups: KOA with MS, KOA without MS and controls group (p < 0.001) In contrast, IL-1β/leptin ratio tended to increase 13 3.3.3 Relationships between plasma leptin and IL-1β concentrations with some clinical and subclinical features in patients with primary knee osteoarthritis Table 3.24 Correlation between leptin with metabolic syndrome components, obesity and some variables Leptin and variables Women Men KOA* (n = 141) (n = 23) (n = 164) r p r p r p Components of metabolic syndrome SBP (mmHg) 0.134 > 0.05 0.030 > 0.05 0.036 > 0.05 DBP (mmHg) 0.091 > 0.05 0.004 > 0.05 -0.019 > 0.05 Glucose (mmol/L) 0.056 > 0.05 0.163 > 0.05 -0.013 > 0.05 Triglyceride (mmol/L) 0.080 > 0.05 0.047 > 0.05 0.014 > 0.05 HDL-C (mmol/L) 0.054 > 0.05 -0.217 > 0.05 0.087 > 0.05 WC (cm) 0.430 < 0.001 0.723 < 0.001 0.417 < 0.001 Weight (kg) 0.459 < 0.001 0.657 = 0.001 0.381 < 0.001 BMI (kg/m2) 0.514 < 0.001 0.548 < 0.01 0.489 < 0.001 Insulin (µU/mL) 0.420 < 0.001 0.668 < 0.001 0.403 < 0.001 HbA1c (%) 0.303 < 0.001 0.114 > 0.05 0.185 < 0.05 HOMA-IR 0.383 < 0.001 0.626 = 0.001 0.346 < 0.001 IL-1β (pg/mL) -0.046 > 0.05 -0.204 > 0.05 -0.046 > 0.05 CRP (mg/L) 0.113 > 0.05 -0.051 > 0.05 0.037 > 0.05 Age (năm) 0.113 > 0.05 -0.337 > 0.05 0.028 > 0.05 Leptin concentrations were positively correlated with markers of obesity and insulin resistance (WC, weight, BMI, insulin, HOMA-IR); were not correlated with MS components (except WC), IL-1β, CRP, age 14 Table 3.25 Multivariate regression equation between leptin with independent variables in women group Variables Beta coefficient standardized p Insulin (µU/mL) 0.760 < 0.001 BMI (kg/m2) 0.216 < 0.01 HOMA-IR -0.397 < 0.05 R2 = 0.298 p ANOVA < 0.001 Leptin = 1.462*insulin + 0.638*BMI – 2.402*HOMA-IR -11.209 Women: insulin, BMI, HOMA-IR affected about 29.8% of the plasma leptin concentrations, in which insulin had the strongest effect Table 3.26 Correlation between IL-1β, IL-1β/leptin with CRP and some other variables IL-1β Tỉ số IL-1β/leptin Variables (n = 164) r p r p CRP (mg/L) -0.100 > 0.05 -0.009 > 0.05 VAS 0.086 > 0.05 0.204 < 0.01 Age (năm) 0.101 > 0.05 -0.012 > 0.05 Components of metabolic syndrome WC (cm) -0.086 > 0.05 -0.365 < 0.001 SBP (mmHg) -0.002 > 0.05 -0.057 > 0.05 DBP (mmHg) -0.064 > 0.05 -0.028 > 0.05 Glucose (mmol/L) -0.070 > 0.05 -0.047 > 0.05 Triglyceride (mmol/L) 0.153 = 0.05 0.066 > 0.05 HDL-C (mmol/L) -0.042 > 0.05 -0.118 > 0.05 BMI (kg/m2) -0.029 > 0.05 -0.390 < 0.001 HbA1c (%) -0.110 > 0.05 -0.218 < 0.01 Insulin (µU/mL) -0.180 < 0.05 -0.432 < 0.001 HOMA-IR -0.189 < 0.05 -0.388 < 0.001 IL-1β concentrations were not correlated with inflamatory marker (CRP), VAS, all components of MS, all markers of obesity and age; Weak negatively correlation with insulin, HOMA-IR IL-1β/leptin ratio inversely correlatedwith WC, BMI, Insulin, HbA1c, HOMA-IR (r from -0,432 to -0,365; p < 0.01) 15 Table 3.27 Variables (n = 164) 4 stages of Xray Early Late Early and late Number of MS components Leptin (ng/mL) Median (Q1 - Q3) IL-1β (pg/mL) Median (Q1 - Q3) (4.2 - 13.1) 9.6 (5.8 - 14.8) 9.9 (5.7 - 14.3) 20.8 (9.4 - 40.5) p > 0.05 9.4 (5.7 - 14.0) 10.4 (6.0 - 14.6) p > 0.05 7.6 (1.2 - 11.1) 7.7 (1.7 - 12.4) 8.3 (4.2 - 11.4) 11.1 (6.0 - 15.0) 9.5 (6.1 - 15.7) 11.5 (7.5 - 16.2) p > 0.05 9.6 (8.6 - 14) 10.1 (8.7 - 13.6) 10.4 (9.1 - 12.5) 9.6 (9 - 11.4) p > 0.05 9.9 (8.7 – 13.8) 10.1 (9.1 - 12.2) p > 0.05 9.8 (8.3 - 10.4) 10 (8.5 - 17.9) 9.7 (8.4 - 11.8) 10.3 (8.4 - 14.3) 10.0 (9.1 - 12.4) 10.0 (9.0 - 15.3) p > 0.05 Median of leptin or IL-1β concentrations were not statistically different in the groups of Xray, early and late, number of MS components Table 3.28 Variables (n = 164) BMI (kg/m2) Number of KOA Duration Leptin (ng/mL) Median (Q1 - Q3) IL-1β (pg/mL) Median (Q1 - Q3) < 23 6.2 (3.4 - 10.3) 10.2 (8.5 - 13.8) 23 - 24.9 9.4 (6.9 - 12.9) 10.1 (8.7 - 13) ≥ 25 13 (10.4 - 15.8) p < 0.001 8.5 (4.0 - 11.9) 10.5 (6.3 - 15.7) p < 0.05 9.2 (5.4 - 13.3) 11.9 (8.7 - 15.6) p < 0.05 9.7 (8.8 - 12.1) p > 0.05 9.6 (8.2 - 12.2) 10.3 (9 - 13.2) p > 0.05 9.2 (8.7 - 14.0) 10 (8.9 - 11.0) p > 0.05 knee knees Short Long 16 Median of leptin concentrations increased gradually when BMI increased, number of KOA, the duration of KOA was long; median of IL-1β concentrations were not statistically different in these groups Table 3.31 The cut-off point of plasma leptin to predict MS Leptin Cut-off (ng/mL) point Men n = 23 women n =141 AUC 95% CI p Sensitivity Specificity 5.5 0.892 0.744 - 1.0 < 0.01 1.0 0.867 8.7 0.643 0.55 - 0.736 < 0.01 0.779 0.516 The cut-off point of plasma leptin concentrations in men KOA was 5,5 ng/mL, in women KOA was 8.7 ng/mL to predict MS CHAPTER 4: DISCUSSION 4.1 General characteristics of patients with knee osteoarthritis 4.1.1 Anthropometric characteristics The mean age was 56.7 ± 8.2, from 37 to 81 years old 86.6% were women Many researchs found that OA was more common in women than men, especially after menopause, which may be related to estrogen deficiency or due to imbalance between bone formation and bone destruction related to leptin Mean BMI was 24.0 ± 3.0 kg/m 2, from 16.3 to 35.7 kg/m2; The proportion of overweight and obese accounted for 61.5%, similar to Bui Hai Binh's 60.7% Mean BMI of men was similar to women group Many researchs find the role of weight or BMI affecting the formation and development of OA, especially in the knee joint 17 4.1.2.Clinical and subclinical symptoms 582 KOA patients with 905 ostoarthritis of the knee joints, the right knee was 446 (49.3%), equivalent to the number of the left knee was 459 (50.7%) All patients had joint pain and short morning stiffness for less than 30 minutes or no stiffness Symptoms of red, hot, swelling, muscular atrophy had below 20% In addition, valgus was more common than varus deformity, the mean VAS and WOMAC scores were lower than the intervention studies The mean plasma CRP concentrations was 2.9 ± 5.3 mg/L, similar to SanchezRamirez D.C was 2.9 ± 3.1 mg/L The mean CRP in the MS group was higher than the non-MS The rate of OA in the early stage (1 and 2) was 75.5% 4.2 The prevalence of metabolic syndrome and the relationship with the stages of primary knee osteoarthritis 4.2.1.Prevalence of metabolic syndrome in knee osteoarthritis MS was present in 51.7% KOA patients using the IDF criteria This prevalence was similar to study of Shin D in Korea (52.4%), ElSaid T.O et al in Egypt (53.7%), Abourazzak F et al in Morocco (48.5%); was higher than study of Xie D.X et al in China (20.3%); was lower than study of Yerima A et al in Nigeria (59.8%) and Puenpatom R.A et al in the US (59%) In many researchs, the ratio of MS in OA was change from 20% to 60%, because the researches used different MS criteria, different OA criteria such as based on clinical and Xray or only based on Xray, different OA stages In women, the incidence of MS in KOA was 55.4%, it was higher than men (28.2%), an odds ratio of 3.2 and 95% CI of 1.9 - 5.3 (p < 0.001), similar to ElSaid T.O et al study (62.4% in women, higher than mens), differ from Niu J., et al the prevalence of MS in men OA was 26.7% higher than in women (22.9%) and Maddah S et al, the prevalence of MS in mens (24.0%) was higher than women (18.3%) Firstly, due to the application of different criteria of MS, we used IDF to take WC as a compulsory standard, while other studies used NCEP to assess equally criteria without mandatory criteria Secondly, our 18 women patients had a mean WC higher than the 80 cm, while the mean WC in the men group was lower than the 90 cm, threshold, the prevalence of MS in the women OA was much higher than men The incidence of MS in KOA with obesity was 72.6%, higher than nonobesity KOA (40.7%) with an odds ratio of 3.9 IDF considers obesity to be the main cause of MS Obesity contributes to hyperglycemia, hypertriglyceridemia, insulin resistance, low HDL-C, hypertension The incidence of MS increases when the OA stage was getting worse (Chart 3.4), which means that when OA was getting worse, the patient had more comorbid conditions such as hypertension, impaired fasting glucose, dyslipidemia The incidence of MS in severe KOA was significantly higher than mild with OR by 2.0 and 95% CI from 1.4 to 2.9 (p < 0.001) (Table 3.13), similaly to Vasilic-Brasnjevic S et al 4.2.2 Relationship between obesity and knee osteoarthritis Obesity was the biggest risk factor for KOA and was an important component of MS The incidence of MS in obesity was higher than the non-obesity group (72.6% vs 40.7%) In this study, the obesity rate was 34.5%; BMI was 24.0 ± 3.0 kg/m 2; increased WC rate was 71.3%; the prevalence of MS in women group was higher than men because of the rate of increased WC in the women was higher than the men group The incidence of both sides KOA in the obese was significantly higher than the one side group with odds ratio of 1.5; Similar conclusions of Sellam J obesity increased the risk of KOA, especially OA knees on both sides We also found abdominal obesity associated with OA but not BMI; Suitable for Vasilic-Brasnjevic et al, abdominal obesity or BMI ≥ 30 kg/m2 strongly correlated with the Xray stage Obesity increased the chronic mechanical pressure at load bearing joints Adipocytokine production, adipocytokines such as leptin, adiponectin they combined with pro-inflammatory cytokines such as IL-1β, TNF-α derived from adipose tissue, causing inflammation of synovial membranes, cartilage degradation; leptin acted directly on connective tissue to promote formation and progression of OA 4.2.3 Relationship between hypertension and knee osteoarthritis 19 The concept of "hypertension" according to the IDF criteria for MS, very differed from the JNC According to IDF, the hypertension rate of KOA was lower than Puenpatom R.A et al (64.3% vs 77.7%) There were very few studies that explain the relationship between hypertension and OA A hypothesis hypertension caused endothelial dysfunction; reduction of neural dynamics, localized perfusion reduction in peripheral organizations including cartilage, reduction of oxygen and nutrient supply, reduction of metabolism between cartilage and covered cartilage In addition, ischemia leaded to apoptosis of subchondral cells and turnover abnormalities 4.2.4 Relationship between plasma sugar and knee osteoarthritis Glucose: The concept of "hyperglycemia" according to the IDF criteria for MS was different from IDF criteria for diabetes The rate of hyperglycemia of patients with KOA was higher than Puenpatom R.A study (43.6% vs 30.7%) It may be due to differences in size and age, glycemia concentrations increased with age • Insulin concentrations: The insulin concentrations of the MS group were higher than the non-MS • HOMA-IR: mean HOMA-IR in the MS group was higher than the non-MS, the men was lower than the women group According to the two meta-analyzes of Louati and Williams, type diabetes was a risk factor for OA Of all components of MS, diabetes alone was considered an independent risk factor for progression of KOA There were two types of type diabetes mechanism acting on joint tissue Firstly, chronic hyperglycemia causes oxidative stress, increased proinflammatory cytokine production, accumulation of AGEs in joint tissue, and differentiation of potential stem cells Secondly, insulin resistance in local synovial membrane of diabetic patients and lowstage systemic inflammation associated with insulin resistance 4.2.5 Relationship between dyslipidemia and knee osteoarthritis 20 Degenerative cartilage reduced regulating gene expression, absorption of cholesterol into cells causes accumulation of cholesterol in chondrocytes (Tsezou A et al) Increasing free fatty acids can cause insulin resistance Treatment of dyslipidemia with statins in OA patients for years that reduce in progress of OA (Wang Y) • Triglyceride: The prevalence of triglyceride in KOA patients was 56.5%, there were no difference between men and women The rate of hypertriglyceride in the obese was statistically higher than the non-obese group; in the group with MS was statistically higher than the non-MS, in the late was statistically higher than early stage • Low HDL-C: The rate of low HDL-C in the MS group was statistically higher than without MS group There was no difference in rate of low HDL-C between late and early groups The rate of increased triglyceride (56.5%) was equivalent to the low HDL-C (54%), similar to Bui Hai Binh study (52.4%) Compared to Gweressus E.D et al, our mean triglyceride was higher, the mean HDL-C was lower This difference may be due to race, Vietnamese people tend to eat more starch, so they tend to have a higher rate of increased triglycerides and lower HDL-C 4.3.Plasma leptin and IL-1β concentrations 4.3.1.Characteristics of disease groups, disease groups*, controls KOA group and KOA* group were similar to gender, age, BMI and rate of MS indicate that the KOA* group was representing the KOA group KOA* group and controls were similar to rate of sex but differences in BMI and rate of MS 4.3.2 Plasma leptin 4.3.2.1 Leptin concentrations in patients with primary knee osteoarthritis KOA* group: leptin concentrations was between 0.07 - 75.8 ng/mL, median 9.5 ng/mL; interval quartile 5.8 - 14.3 ng/mL; mean 11.5 ± 10.0 ng/mL; it was similar to result of Zheng S (10.65 ± 13.10 ng/mL); lower than most published results, probably due to 21 differences in obesity criteria, mean BMI in these studies were higher in our study, which leptin correlated with BMI Leptin concentrations in KOA* group had median value and interquartile range of 9.5 (5.8 - 14.3) ng/mL, significantly higher than the controls of 0.5 (0.3 - 0.7) ng/mL Leptin concentrations were highest in the KOA group with MS, higher than the KOA group without MS, the lowest in the healthy controls (p < 0.001) This suggests that leptin had an intermediate role in the relationship between leptin and MS and OA However, this was a cross-sectional study, so it was not possible to determine the causal relationship of leptin-induced OA or OA causing increased leptin-associated MS 4.3.2.2 Factors affecting leptin concentrations in KOA patients • Leptin and sex: In women, leptin concentrations were higher than men in both KOA* and controls groups In women, leptin was always higher than men, regardless of OA status Due to the effects of sex hormones, leptin was two to three-fold higher in women than men, who had the same amount of fat • The correlation between leptin and BMI: a moderate positive correlation between leptin and BMI (r = 0.489 and p < 0.001), similar to result of Staikos C et al (r = 0.49 and p < 0.01) and slightly less than Manoy’ results (r = 0.57 p < 0.001) • Correlation between leptin and WC: moderate positive correlation between leptin and WC (r = 0.417 and p < 0.001), similar to result of Manoy P (r = 0.49 and p < 0.001), this correlation was even more powerful if considered separately in the men group, the correlation was tight (r = 0.723 and p < 0.001) • Correlation between leptin and weight: moderate positive correlation between leptin and weight (r = 0.459 and p < 0.001); similar to result of Iwamoto J (r = 0.392 and p = 0.0084) • Leptin and insulin resistance: a positive correlation between leptin and HOMA-IR (r = 0.346 and p < 0.001); particularly, in men group achieved a relatively positive correlation (r = 0.626 and p = 0.001), moderate positive correlation in the women; A moderate 22 positive correlation between leptin and insulin (r = 0.403 and p < 0.001); particularly, the men group correlated quite tightly (r = 0.668 and p = 0.001), in the women, the correlation was medium There was no correlation between leptin and glucose and HbA1c, similar to two studies of Vo Minh Phuong and Nguyen Van Hoan • Leptin and blood pressure, lipids profile: no correlation 4.3.2.3 The cut-off points of leptin predict the risk of MS In women KOA group: the cut-off point of leptin concentrations that predicted MS was 8.7 ng/mL with AUC was 0.643; sensitivity was 77.9%; specificity was 51.6% and p