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.
.MINISTRY OF EDUCATION AND MINISTRY OF TRAINING DEFENCE VIETNAM MILITARY MEDICAL UNIVERSITY NGUYEN THI THANH MAI METABOLIC SYNDROME, PLASMA LEPTIN AND IL1β CONCENTRATIONS IN PATIENTS WITH PRIMARY KNEE OSTEOARTHRITIS Speciality : INTERNAL MEDICINE Code : 9 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 lowstage 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 nonOA group. Obesity was a significant risk factor for knee OA (KOA) through mechanisms of increasing mechanical load and chronic lowstage inflammation Lowstage chronic inflammation associated with adipokines (leptin) interacts with proinflammatory cytokines of which interleukin1β (IL1β) was a key role in maintaining cartilage ulcers, substrate degradation in obesity pathogenesis mechanism caused OA Therefore, the thesis “Metabolic syndrome, plasma leptin and IL1β 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 IL1β 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, lowstage chronic inflammatory response and adipokines (leptin) or proinflammatory cytokines (IL1 β) * The practical significance: Described the specific value of the prevalence of MS, plasma leptin and IL1β 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 do 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 IL1β 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 IL1β concentrations of the KOA patients were higher than the control; the correlation between leptin and IL1β were determined with some metabolic risk factors. Determination of the cutoff 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 1 Overview: 35 pages, Chapter 2 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. Lowstage chronic inflammation Adipokines (leptin, resistin ) and proinflammatory cytokines (TNFα, IL1β, IL6 ) were related to the common mechanism of MS and OA Hypothesis on the independent role of lowstage chronic systemic related to obesity and MS were caused the onset of OA 1.1.2.2. Proinflammation cytokine (IL1β) IL1β was a strong proinflammatory 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. IL1β stimulated IL6 and IL8 production; contributed to inflammation (localized in synovial or systemic inflammation). Chondrocytes were the main target cells of IL1β, degenerative chondrocytes were higher sensitive to the effects of IL1β 3 to 4fold than normal chondrocytes Only 1% of IL1β receptors on active cartilage surface can convert chondrocytes into a form of strong catabolism. 1.1.2.3. Adipokine (Leptin) Leptin was an energyregulating hormone, also a pro inflammatory 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 IL1β, MMP9, MMP13 , contributing to cartilage degradation. Leptin caused cell proliferation, increased collagen synthesis, stimulated endothelial calcium, increased bone mineralization, increased growth factor IGF1 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 lowbiomechanics and chronic inflammation Adipose tissue produced adipocytokines such as leptin in combination with proinflammatory 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 pro inflammatory cytokine production, AGEs accumulation in joint tissues, and differentiation of potential stem cells, insulin resistance at local synovial membranes and lowstage 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 nonOA, one person with OA in middle age had a risk of MS increased 5.26fold 1.4.2. Leptin and osteoarthritis researches Leptindeficient (ob/ob) and leptin receptordeficient (db/db) female mice compared with wildtype 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. IL1β and osteoarthritis researches Ning L. et al found IL1β concentrations related to the severity of the disease so it was a marker for the severity of OA. Nguyen Ngoc Chau found that plasma IL1β 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 crosssectional 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 × p × (1p) d2 Sample size for aim 2: σ = 0.3 d = 0.05 = 0.05 n = 138.3 n = /2) Z2(1 n = × σ2 /2) d 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 IL1β plasma Plasma leptin test by the Human leptin ELISA kit of Sigma; plasma IL1β test by Human IL1β 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, HDLC, triglyceride, glucose, HbA1c, insulin … KOA KOA* (n = 582) (n = 164) To determine the prevalence of MS, its components and the relationship with the stages of primary KOA CONTROLS healthy people (n = 78) Leptin, IL 1β 2. 2. To determine the relationship of 14 KOA*: Leptin concentrations in MS group were higher than the nonMS; IL1β were not statistically different. IL1 β/leptin ratio in the KOA without MS was higher than the KOA with MS Table 3.21. Leptin, IL1β, IL1β/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 IL1β 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 IL1β /leptin Q1 Q3 9.6 24.9 27.2 227.5 9.4 19.2 p 0.05 0.05 0.013 > 0.05 Triglyceride (mmol/L) 0.080 > 0.05 0.047 > 0.05 0.014 > 0.05 HDLC (mmol/L) 0.054 > 0.05 0.217 > 0.05 0.087 > 0.05 WC (cm) 0.430 0.05 0.047 > 0.05 Triglyceride (mmol/L) 0.153 = 0.05 0.066 > 0.05 HDLC (mmol/L) 0.042 > 0.05 0.118 > 0.05 BMI (kg/m2) 0.029 > 0.05 0.390 0.05 0.218 0.05 18 Median of leptin or IL1β 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 Leptin (ng/mL) Median (Q1 Q3) IL1β (pg/mL) Median (Q1 Q3)