Relationship between Metabolic Syndrome and Diffuse Idiopathic Skeletal Hyperostosis in Sample of Iraqi Patients

Diffuse idiopathic skeletal hyperostosis is a non-inflammatory disease characterised by calcification of soft tissues, mainly ligaments and enthuses, as well as by ossification of the anterior longitudinal ligament. To assess the relationship between Metabolic Syndrome and Diffuse Idiopathic Skeletal Hyperostosis among a sample of middle and old age Iraqis.A cross-sectional study was conducted from October 2018 to May 2019 at the Rheumatology Unit of Baghdad Teaching Hospital, Iraq and Basra Teaching Hospital, Iraq. A total of 282 patients were included in the study. Data were gathered using a pre-constructed data collection sheet for patients that evaluate: age, gender, occupation, education, smoking, weight, height, waist circumference, and body mass index were calculated. Clinical data about back pain, limitation in movement or any neurological symptoms were identified, serum lipid profiles (serum triglycerides, serum high-density lipoprotein), fasting blood sugar, haemoglobin A1c and serum uric acid were obtained. Diffuse Idiopathic Skeletal Hyperostosis was reported in 18 (6.4%) patients. High waist circumference was reported in 175 patients, high triglycerides found in 208 patients, while low HDL found in 162 patients. We reported 147 patients who had elevated blood pressure and 106 patients with elevated blood glucose. Diffuse Idiopathic Skeletal Hyperostosis was significantly more frequent in patients with metabolic syndrome compared to those with no metabolic syndrome, (9.2%) vs (3.1%). There is a significant association between diffuse idiopathic skeletal hyperostosis and metabolic syndrome among a sample of middle and old age Iraqi people.

back pain, diffuse idiopathic skeletal hyperostosis, metabolic syndrome ABSTRACT Diffuse idiopathic skeletal hyperostosis is a non-in lammatory disease characterised by calci ication of soft tissues, mainly ligaments and enthuses, as well as by ossi ication of the anterior longitudinal ligament. To assess the relationship between Metabolic Syndrome and Diffuse Idiopathic Skeletal Hyperostosis among a sample of middle and old age Iraqis.A cross-sectional study was conducted from October 2018 to May 2019 at the Rheumatology Unit of Baghdad Teaching Hospital, Iraq and Basra Teaching Hospital, Iraq. A total of 282 patients were included in the study. Data were gathered using a pre-constructed data collection sheet for patients that evaluate: age, gender, occupation, education, smoking, weight, height, waist circumference, and body mass index were calculated. Clinical data about back pain, limitation in movement or any neurological symptoms were identi ied, serum lipid pro iles (serum triglycerides, serum high-density lipoprotein), fasting blood sugar, haemoglobin A1c and serum uric acid were obtained. Diffuse Idiopathic Skeletal Hyperostosis was reported in 18 (6.4%) patients. High waist circumference was reported in 175 patients, high triglycerides found in 208 patients, while low HDL found in 162 patients. We reported 147 patients who had elevated blood pressure and 106 patients with elevated blood glucose. Diffuse Idiopathic Skeletal Hyperostosis was signi icantly more frequent in patients with metabolic syndrome compared to those with no metabolic syndrome, (9.2%) vs (3.1%). There is a signi icant association between diffuse idiopathic skeletal hyperostosis and metabolic syndrome among a sample of middle and old age Iraqi people.

INTRODUCTION
Diffuse idiopathic skeletal hyperostosis (DISH) is a non-in lammatory disease characterised by calci ication and ossi ication of the spinal ligaments and regions where tendons and ligaments attach to bone (Hannallah et al., 2007). This condition is characterised by lowing ossi ications on the anterolateral side of at least four contiguous vertebrae. Mainly in the thoracic spine with relative preservation of the intervertebral disc (IVD), the new bone formation is most frequently observed on the right side of the thoracic spine. Aortic pulsations have been suggested to prevent ossi ication on the left side (Kim et al., 2018).
Diffuse Idiopathic Skeletal Hyperostosis (DISH) has been linked to metabolic and constitutional factors such as obesity, high waist circumference, hypertension, type 2 Diabetes mellitus, hyperinsulinemia, dyslipidemia, elevated growth-promoting peptides, hyperuricemia. The association of DISH with excess body weight has been well known since the early descriptions by Forestier and other investigators (Pariente-Rodrigo et al., 2017). It has been assumed that the high serum insulin levels in type 2 D.M. may contribute to the formation of DISH (Mader et al., 2017).
Relationship between the metabolic syndrome and diffuse idiopathic skeletal hyperostosis: Both metabolic syndrome (M.S.) and DISH sharply increase with old age group. Previous research con irmed the association of metabolic factors as risk factors for DISH (Pillai and Littlejohn, 2014). Metabolic abnormalities have been reported to be associated with DISH, including obesity, high waist circumference, hypertension, diabetes mellitus, hyperinsulinemia, and dyslipidemia (Srikanthan et al., 2016). The metabolic factors present in patients with DISH, such as insulin, likely interact with key candidate cellular targets linking to new bone formation, these include chondrocytes and periosteal mesenchymal cells within the enthesis (Han and Lean, 2016).

Study design and setting
A cross-sectional study was conducted at the Rheumatologic unit in Baghdad Teaching Hospital, and Al Sader Teaching Hospital, during the period from October 2018 to May 2019.

Study population
A total of 282 patients were involved in the study. Women were 208 (73.8%).

Inclusion criteria
All patients aged ≥50 years who had back pain and/ or limit the range of motion of the spine were included.

Exclusion criteria
Patients with one or more of the following criteria were excluded from the study 1. Congenital diseases of the lumbar spine. 5. In lammatory diseases of the spine (seronegative spondyloarthropathy).

Data collection
Data were collected using a data collection sheet containing questionnaires for the patients. The questionnaires included the irst part for the general demographic data: name, age, gender, height, weight, body mass index (measured for all patients according to the equation BMI=weight/ height 2 ), waist circumference, residence (urban, rural), employment (employed, unemployed), marital status (unmarried, married, widow, and divorced) and smoking status (current smoker, ex-smoker, never). The second part for clinical and laboratory data about back pain (cervical, dorsal, lumbar), limitation of movement, dysphagia, neurological symptoms (numbness, paresthesia, loss of sphincter, saddle anaesthesia, paralysis), X-ray inding, Hb A1C, blood pressure, serum triglyceride, serum uric acid, serum high-density lipoprotein (HDL), serum fasting blood sugar were measured.

Clinical methodology
Standing height was measured in centimetres using a stadiometer, and body weight was measured in kilograms (kg) with light clothes and without shoes using a weighing scale. Waist circumference was measured in centimetres at the end of the normal expiration with tap placed horizontally midway between the subcostal margin and the iliac crest in a standing position (to assess central obesity (which de ined as >102 cm in men and >88 cm in women according to National Cholesterol Education Program ATP-Third criteria for M.S.). Bodyweight classi ied according to body mass index (BMI); normal (BMI 18.5-24.9 kg/m2), underweight (BMI <18.5 kg/m2), overweight (BMI 25-29.9 kg/m2), obese (BMI 30-40 kg/m2), and morbidly obese (BMI >40 kg/m2). Blood pressure measurement was done by using a mercury sphygmomanometer in either arm when the patient relaxed in sitting position and his feet on the ground, and the arm at the level of the

Laboratory methodology
Blood samples were collected from all individuals under aseptic venipuncture for measuring HbA1C, triglyceride, HDL, fasting blood sugar used an instrument SIEMENS-RXL-MAX-224514-AX made in the USA at Bagdad Teaching Hospital, and ADAVMS-A1C/HA-8160 made in Japan ARKRAY 2013 at Basra Teaching Hospital.

Radiological Methodology
Plain X-ray was performed to all patients in the form of lateral and anteroposterior views of dorso lumbar spine or cervicodorsal used Digital AGFA/ DX-D400 made in Belgium 2013 in Bagdad Teaching Hospital, and Digital KL/W-500 made in Japan 2014 in Basra Teaching Hospital.

Diagnosis of DISH based on reliant on Resnick and
Niwayama's (1976) highly speci ic criteria. Diagnostic criteria of M.S. was considered according to the NCEP ATP III criteria (Alberti, 2005).
After approval of the presence or absence of DISH and M.S., the study participants categorised into four subgroups according to their indings; DISH with M.S., DISH without M.S., no DISH with M.S., no DISH without M.S. and these are the only possible combinations.

Statistical analysis
Data of patients were checked for any errors or inconsistencies then transferred into a computerised statistical software; statistical package for social sciences (SPSS) version 25 was used in all statistical analyses and procedures. Descriptive statistics were presented as mean ± standard deviation (S.D.), frequencies (number of cases) and proportions (percentages). Chi-square (X 2) was used to ind the signi icance of the relationship between metabolic syndrome and DISH. Odds' ratio was calculated, which is an estimator of the risk of occurrence of an event in a group compared to another group. Value of OR more than once indicated that the factor under study (M.S.) is a risk factor to the outcome (DISH), and the result is more likely to occur among the exposed group. Binary logistic regression was performed to control the possible confounding effect of other variables (age, gender, occupation, education, smoking, hypertension, and D.M.). On the correlation between M.S. and DISH. The level of signi icance (P. value) of < 0.05 con-sidered as signi icant. Finally, the results were presented in tables and or igures with an explanation for each table.

RESULTS AND DISCUSSION
There were 282 patients enrolled in this study with a mean age of 52.7 ± 8.1 years. Women were dominant, represented 73.8% (Table 1). Patients with three or more criteria (i.e. with metabolic syndrome) were 153 represented (54.3%) of the studied group (Figure 2). To assess the relationship between Metabolic Syndrome and DISH among the studied group, crosstabulation was performed for DISH as a disease against M.S. as the risk factor, ( Table 5), results of this analysis revealed that DISH was signi icantly more frequent in patients with metabolic syndrome compared to those with no metabolic syndrome, (9.2%) vs (3.1%), respectively, (P. value = 0.038). Moreover, odds' ratio was calculated, and it was 3.15, which indicated that patients with M.S. were about three folds more likely to have DISH compared to healthy population (without M.S.).
Further analysis was performed using the binary logistic regression to control the possible confounding effect of other variables that may interfere with the correlation between DISH and M.S. Results of this analysis is shown in (Table 6) where the relationship between metabolic syndrome and presence of DISH still signi icant (P. value = 0.030) after adjustment for other variables (age, gender, occupation, education, smoking, hypertension and D.M.).
There are few published data available concerning the association between Diffuse Idiopathic Skeletal Hyperostosis and MS. Up to the best of our knowledge there was no local or regional study discussed the relationship between the DISH and M.S. In this study the mean age was ( 52.7 ± 8.1) years, which agree with Sruti P.et al ( Australia) (Pillai and Littlejohn, 2014) who reported [mean age ± standard deviation = 50 ± 33.8], that con irmed that DISH is more common at age >50 years. These results differed from the cohort study done by Mader I. et al. (Israel) (Mader and Lavi, 2009) who identi ied 18 (12.8%) patients were diagnosed before the age of 50 years. This discrepancy explains that they used long cohort study comparing group A (18 patients with DISH diagnosed before the age of 50 years), group B (20 patients of similar age with osteoarthritis), and group C (24 patients with DISH diagnosed after the age of 60 years). In the current study, 18/ 282 patients had DISH, which represented 6.4% of the studied group. This inding was similar to the results of Sruti P. et al. (Pillai and Littlejohn, 2014) who reported 19 (7%) cases of DISH in 265 patients. We reported 14 cases of DISH and have MS, 4 cases of DISH without M.S., which was statistically signi icant and was in agreement with Mader I. et al. (Israel) (Mader and Lavi, 2009) and Sruti P. et al. (Pillai and Littlejohn, 2014), and this suggests that DISH was more common in M.S. than the general population. In light of our indings, we found 11 men had DISH, and seven women also had DISH which means that DISH more common in men which agree with Hiromitsu T.et al (Toyoda et al., 2017) in which the men were predominant and percentage of DISH in men and women above 50 years was 35% vs 15% respectively. Increased waist circumference (for man ≥  (Mansour et al., 2007). Elevated triglycerides were reported in 73.8% patients, while reduced HDL (< 40 mg/ dl in man and < 50 mg/dl in the women) was found in 57.4% and that agree with Sruti P. et al. (Pillai and Littlejohn, 2014). I n the current study we found elevated blood pressure in 52.1% patients and high fasting blood glucose was found in 37.6% of patients, and these results were closest to Sruti P.et al (Pillai and Littlejohn, 2014). In light of our indings, we found 54.3% of individuals of the studied group had M.S., which is closest to Al-Thani M. et al. study (Al-Thani et al., 2016). But our results disagree with Ismael S.et al (Ismael et al., 2016) in Iraq which showed the prevalence of metabolic syndrome was 30.6%. It was higher in women (45.5%) than men (16.3%). This discrepancy because of the difference in the mean age (± S.D.) and also may be due to differences in the prevalence of obesity, sedentary lifestyle, family history of speci ic cardiovascular, D.M., hyperlipidemia, hypertension and physical inactivity which is used as risk factors for M.S. in this study. In this study we showed that 83.3% of patients with DISH had increase waist circumference, 66.7 % had increase serum triglycerides, 44.4 % had reduced serum HDL, 61.1% had elevated blood pressure, and 27.8% had elevated serum fasting blood sugar. These results were statistically signi icant and similar to Sruti P.et al (Pillai and Littlejohn, 2014) which showed a strong association between DISH and insulin intolerance and other components of M.S.
The Relationship between DISH and M.S. still signi icant after adjustment for other variables (age, gender, occupation, education, smoking, hypertension and D.M.) using the binary logistic regression to control the possible confounding effect and found no impact of these variable. There was disagreement with Abdul Rudha S. et al. (Iraq) (Abdulsada et al., 2017) study which showed that epidemiological factors (age, sex, occupation, and family history of diabetes) were strongly related to M.S. These differences arose because Abdul-rudha S. et al. used two groups as control and used other variables like young age women with beta-thalassemia disorder. Also, our results disagree with Mader I. et al. (Mader and Lavi, 2009) in considering age, gender and occupation as essential risk factors affect the relationship between DISH and M.S. and that are because in our current study we used a cross-sectional survey while Mader I. et al. used a cohort study design and long length of follow up.
We found that DISH was signi icantly more frequent in patients with metabolic syndrome com-pared to those with no metabolic syndrome, (9.2%) vs (3.1%), respectively. Patients with M.S. were about three folds more likely to have DISH compared to healthy population (without M.S.) this agreed with other studies as Mader I. et al. (Mader and Lavi, 2009) and Sruti P.et al. (Pillai and Littlejohn, 2014).

CONCLUSIONS
Diffuse Idiopathic Skeletal Hyperostosis was signi icantly more frequent in individuals with M.S. compared to those with no M.S. Patients with DISH have a high rate of central obesity, dyslipidemia and insulin intolerance. We also demonstrated the need for further studies to a better-de ined background of M.S. factors that promote the new bone formation, which characterises DISH.