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

VIETNAM MILITARY MEDICAL UNIVERSITYNGUYEN THI THANH MAI METABOLIC SYNDROME, PLASMA LEPTIN AND IL-1β CONCENTRATIONS IN PATIENTSβ CONCENTRATIONS IN PATIENTS WITH PRIMARY KNEE OSTEOARTHRITI

VIETNAM MILITARY MEDICAL UNIVERSITY

NGUYEN THI THANH MAI

METABOLIC SYNDROME, PLASMA LEPTIN AND IL-1β CONCENTRATIONS IN PATIENTSβ CONCENTRATIONS IN PATIENTS WITH PRIMARY KNEE OSTEOARTHRITIS

Speciality : INTERNAL MEDICINECode : 9 72 01 07

THE SUMMARY OF THE MEDICAL DOTORAL THESIS

HANOI – 201β CONCENTRATIONS IN PATIENTS9

Scientific Instructors:

1β CONCENTRATIONS IN PATIENTS A/PROF Ph.D Do Trung Quan

2 A/PROF Ph.D Dao Hung Hanh

1β CONCENTRATIONS IN PATIENTS st Contradictor: A/PROF Ph.D Nguyen Thanh Thuy

2 nd Contradictor: PROF Ph.D Vo Tam

3 rd Contradictor: A/PROF Ph.D Doan Van De

The doctoral thesis will be reported to The Grading andExaminations Committee hold at Vietnam Military MedicalUniversity at 2019

Searching for the dissertation at:

- National Library

- Vietname Military Medical University’s library

Osteoarthritis (OA) was the result of interaction betweenbiomechanics and chronic low-stage inflammation Metabolic syndrome(MS) included central obesity, dyslipidemia, impaired fasting glucose,and hypertension in which obesity was the most important Theprevalence of MS increased in the OA compared with the non-OAgroup Obesity was a significant risk factor for knee OA (KOA) throughmechanisms of increasing mechanical load and chronic low-stageinflammation Low-stage chronic inflammation associated withadipokines (leptin) interacts with pro-inflammatory cytokines of whichinterleukin1β (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 PATIENTSβ concentrations in patients with primary knee osteoarthritis”

was conducted with two objectives:

1 To determine the prevalence of metabolic syndrome, its components and the relationship with the stages of primary knee osteoarthritis.

2 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 mechanismrelated to obesity, low-stage chronic inflammatory response andadipokines (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 andcompared with the control It was recommended to identify a KOApatient with MS accompanying control of two problems simultaneously.Leptin should be quantified in patients with KOA who do not meet thediagnostic criteria for MS, to determine a group of KOA patients at highrisk of MS, for early intervention

* New contributions of this doctoral thesis

This was the first scientific study in Vietnam on MS, plasma leptinand IL-1β concentrations in patients with primary KOA The prevalence

of MS in KOA was 51.7% and its increased when the stage of KOAincreased

Determination of plasma leptin and IL-1β concentrations of the KOApatients were higher than the control; the correlation between leptin andIL-1β were determined with some metabolic risk factors Determination

of the cut-off point of plasma leptin concentrations that predicts a patientwith 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 3 Results: 32 pages, Chapter 4 Discussion: 37 pages,Conclusion: 02 pages, Recommendations: 01 page It includes 33tables, 9 graphs, 16 figures, 1 diagram and 174 references (7Vietnamese references and 167 English references)

CHAPTER 1β CONCENTRATIONS IN PATIENTS: OVERVIEW 1β CONCENTRATIONS IN PATIENTS.1β CONCENTRATIONS IN PATIENTS 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 MSand OA Hypothesis on the independent role of low-stage chronicsystemic 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 theearly stages of OA because it was not only increased cartilagecatabolism (inhibiting type II collagen and aggrecan synthesis leads

to substrate degeneration) but also inhibited cartilage anabolic IL-1βstimulated IL-6 and IL-8 production; contributed to inflammation(localized in synovial or systemic inflammation) Chondrocytes werethe main target cells of IL-1β, degenerative chondrocytes were highersensitive to the effects of IL-1β 3 to 4-fold than normal chondrocytes.Only 1% of IL-1β receptors on active cartilage surface can convertchondrocytes into a form of strong catabolism

1.1.2.3 Adipokine (Leptin)

Leptin was an energy-regulating hormone, also a inflammatory factor that caused inflammation and catabolism ofchondrocytes Leptin resistance was the action of leptin that failedwhen leptin concentrations increased There was still controversyabout leptin causing degeneration or repair of cartilage

pro-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 tocartilage degradation Leptin caused cell proliferation, increased collagensynthesis, 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 thatdevelop cortical bone, collagen synthesis and bone mineralization,stimulating the formation of cartilage

1β CONCENTRATIONS IN PATIENTS.2 Metabolic syndrome

Metabolic syndrome, whose elements include central obesity,dyslipidemia, impaired fasting glucose, and hypertension, increasesthe risk of cardiovascular disease and mortality In this study, MSwas diagnosed according to IDF criteria

1β CONCENTRATIONS IN PATIENTS.3 Relationship between metabolic syndrome and osteoarthritis

1.3.1 Obesity and osteoarthritis

Obesity contributed to OA through low-biomechanics and chronicinflammation Adipose tissue produced adipocytokines such asleptin in combination with pro-inflammatory cytokines such as IL-

1 derived from macrophages in adipose tissue, causing inflammation

of synovial membranes, cartilage degeneration, changes insubchondral bone that caused OA

1.3.2 Glucose, insulin resistance and osteoarthritis

Chronic hyperglycemia caused oxidative stress, increased inflammatory cytokine production, AGEs accumulation in jointtissues, and differentiation of potential stem cells, insulin resistance

pro-at local synovial membranes and low-stage chronic inflammpro-ation

1.3.3 Lipid and osteoarthritis

There were many epidemiological and experimental evidence of

dyslipidemia related to OA Lipid deposition in chondrocytesoccurred 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 ofneural dynamics, localized perfusion reduction in peripheralorganizations including cartilage, reduction of oxygen and nutrientsupply, reduction of metabolism in cartilage In addition, localischemia led to apoptosis of subcutaneous bone cells and subcorticalbone abnormalities

1β CONCENTRATIONS IN PATIENTS.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% inthe non-OA, one person with OA in middle age had a risk of MSincreased 5.26-fold

1.4.2 Leptin and osteoarthritis researches

Leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) femalemice compared with wild-type mice were studied Extreme obesity due

to impaired leptin signaling induced alterations in subchondral bonemorphology without increasing the incidence of knee OA Systemicinflammatory cytokine levels remained largely unchanged in ob/ob anddb/db mice These findings suggest that body fat, in and of itself, maynot be a risk factor for joint degeneration, because adiposity in theabsence of leptin signaling is insufficient to induce systemicinflammation 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 wasassociated with increased KOA in men, increased leptin levels wasassociated 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 ofthe disease so it was a marker for the severity of OA Nguyen NgocChau found that plasma IL-1β concentrations in OA patients was higherthan the controls

CHAPTER 2: SUBJECTS AND METHODS

2.1β CONCENTRATIONS IN PATIENTS Subjects

582 primary KOA patients and 78 healthy control individualswere 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

Sample size for aim 1: p = 0.59 d = 0.04  = 0.05 n = 580.8

We selected 582 patients in the KOA group

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, usinghuman monoclonal antibodies

To determine the prevalence

of MS, its components and

the relationship with the

stages of primary KOA

2 2 To determine the relationship of plasma leptin and IL-1β concentrations with some clinical and subclinical features

in patients with primary KOA

Diagnosis of KOA

Leptin, 1β

IL-WC, blood pressure, HDL-C, triglyceride, glucose, HbA1c, insulin

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/m2

Table 3.6 No statistical differences between the mean ages, BMI,

WC, WHR, hypertension, HbA1c, CRP between men and womengroups

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

n (%)

Women(n = 504)

n (%)

Men(n = 78)

hypertension, high fasting glucose, high triglycerides, obese betweenmen and women

Chart 3.1 The prevalence of MS and its components by obese

The prevalence of MS, high WC, hypertension, high triglyceride,low HDL-C in the obese was higher than in the non-obese, butprevalence of hyperglycemia in two groups were the same

Chart 3.4 The prevalence of metabolic syndrome increased when the knee osteoarthritis stages increased

Table 3.13 The prevalence of MS, high WC, hypertension, high

fasting glucose, high triglycerides in the late stage was statisticallyhigher than in the early stage

Variables

Late (n = 148)

Early (n = 434) p OR (95% CI)

MS 95 (64.2) 206 (47.5) < 0.001β CONCENTRATIONS IN PATIENTS 2.0 (1.4 - 2.9)

High WC 123 (83.1) 292 (67.3) < 0.001β CONCENTRATIONS IN PATIENTS 2.4 (1.5 - 3.9)

Hypertension 111 (75.0) 263 (60.6) < 0.05 2.0 (1.3 - 3.0)

Hyperglycemia 76 (51.4) 178 (41.0) < 0.05 1β CONCENTRATIONS IN PATIENTS.5 (1.04 - 2.2)

High TG 96 (64.9) 233 (53.7) < 0.05 1β CONCENTRATIONS IN PATIENTS.6 (1.1 - 2.3)

Low HDL-C 83 (56.1) 231 (53.2) > 0.05 1.1 (0.8 - 1.6)

3.3 Plasma leptin and IL-1β CONCENTRATIONS IN PATIENTSβ concentrations

3.3.1 Characteristics of research groups

Table 3.15 The KOA* was similar to the KOA in mean age,

BMI, gender ratio and the prevalence of MS The KOA* was similar

to the controls in gender ratio, but the difference in mean age, BMIand the prevalence of MS

3.3.2 Plasma leptin and IL-1β) concentrations in primary knee osteoarthritis compared with controls.

Table 3.17 Leptin, IL-1β, IL-1β/leptin in KOA* by obese

Variables

(n = 164)

Obese (n = 59)Median (Q1 - Q3)

Non obese (n = 105)Median (Q1 - Q3) pLeptin

(ng/mL) 1β CONCENTRATIONS IN PATIENTS3.0 (10.4 - 15.8) 7.9 (4.5 - 11.5) < 0.001β CONCENTRATIONS IN PATIENTSIL-1β (pg/mL) 9.7 (8.8 - 12.1) 10.1 (8.6 - 13.4) > 0.05IL-1β /leptin 0.8 (0.6 - 1.5) 1β CONCENTRATIONS IN PATIENTS.4 (0.9 - 3.3) < 0.001β CONCENTRATIONS IN PATIENTS

KOA*: Leptin concentrations in the obese were higher than in thenon-obese; IL-1β were not statistically different IL-1β/leptin ratio inthe non-obese was higher than in the obese

Table 3.18 Leptin, IL-1β, IL-1β/leptin in KOA* by MS

Variables

(n = 164)

OA with MS (n = 85) Median (Q1 - Q3)

OA without MS (n = 79)

KOA*: Leptin concentrations in MS group were higher than thenon-MS; IL-1β were not statistically different IL-1β/leptin ratio inthe KOA without MS was higher than the KOA with MS

Table 3.21 Leptin, IL-1β, IL-1β/leptin in controls

(n = 78)

Men(n = 11)

IL-1β /leptin Q1 - Q3 9.6 - 24.9 27.2 - 227.5 9.4 - 19.2

Controls: Leptin concentrations in women was significantly higherthan in men; IL-1β were not significantly different; IL-1β/leptin ratio inthe men was higher than in the women

Table 3.22 Leptin, IL-1β, IL-1β/leptin in KOA* and controls

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 groupsleptin in three groups

Variables

OA withMS(n = 85)

7.7(3.9 - 11.4)

9.8(8.6 - 12.0)

1.4(0.8 – 3.4)

13.9

The concentrations of leptin and IL-1β tended to decrease in threegroups: KOA with MS, KOA without MS and controls group (p <0.001) In contrast, IL-1β/leptin ratio tended to increase