Acta Ophthalmologica 2014
Metabolic syndrome as a risk factor in normal-tension glaucoma Mijin Kim,1,2 Jin Wook Jeoung,1,2 Ki Ho Park,1,2 Won Hyuck Oh,3 Hyuk Jin Choi1,4 and Dong Myung Kim1,2 1
Department Department 3 Department 4 Department 2
of of of of
Ophthalmology, Ophthalmology, Ophthalmology, Ophthalmology,
Seoul National University College of Medicine, Seoul, Korea Seoul National University Hospital, Seoul, Korea Inje University Sanggye Paik Hospital, Seoul, Korea Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea
ABSTRACT. Purpose: To determine whether normal-tension glaucoma (NTG) is associated with metabolic syndrome and to evaluate which components of metabolic syndrome are related to NTG. Methods: This study included 18240 participants who underwent health check-ups including fundus photography and intraocular pressure measurements. For NTG diagnosis, all participants with findings suggestive of glaucoma completed a further glaucoma evaluation, including applanation tonometry, gonioscopy and standard automated perimetry. The National Cholesterol Education Program Adult Treatment Panel III guideline was used to characterize metabolic syndrome. Results: Of the 18240 participants, 3635 (19.9%) had metabolic syndrome and 300 (1.6%) were diagnosed with NTG. The prevalence of NTG was 1.5% in subjects without metabolic syndrome and 2.1% in subjects with metabolic syndrome. The presence of metabolic syndrome was not significantly associated with NTG (p = 0.067). There were significant associations of NTG with hypertension and impaired glucose tolerance (IGT) among the individual components of metabolic syndrome (OR, 1.53; 95% CI, 1.20–1.94; p = 0.001 and OR, 1.47; 95% CI, 1.12–1.94; p = 0.006). NTG was positively associated with the number of metabolic syndrome components (OR, 1.10; p = 0.040). Multivariable analysis showed the prevalence of NTG to be significantly higher in participants aged between 50 and 70 years relative to those aged 40 to 50 years, male gender, participants with higher baseline intraocular pressure, hypertension and IGT. Conclusions: Of the metabolic syndrome components, hypertension and IGT contributed to an increased risk of NTG. These findings suggest that metabolic syndrome components may play a role in the pathogenesis of NTG. Key words: diabetes – hypertension – metabolic syndrome – normal-tension glaucoma
Acta Ophthalmol. ª 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
doi: 10.1111/aos.12434 This study was supported by a grant of the Korea Health technology R&D Project, Ministry of Health & Welfare, Republic of Korea [Grant No: A121615 and A101310].
Introduction Normal-tension glaucoma (NTG), a subset of open-angle glaucoma
(OAG), is an entity with progressive glaucomatous optic neuropathy and corresponding visual field defects, but
with intraocular pressure (IOP) within the statistically normal range (Shields 2008). Because patients with NTG have normal IOP, vascular abnormalities such as vasospasms or ischaemia are thought to play an important role in the pathogenesis of NTG (Caprioli & Spaeth 1984). Disc haemorrhage (DH), which is more frequently observed in patients with NTG than in patients with high-tension glaucoma, is suggested to be a consequence of hemodynamic disturbances, including ischaemic microinfarction in the optic nerve head (Begg et al. 1971), disorders of retinal circulation (Sonnsjo & Krakau 1993), decrease in capillary perfusion (Kurvinen et al. 2010) and primary vascular dysregulation (Grieshaber et al. 2006), although the pathogenesis of DH is not yet fully understood. Metabolic syndrome is a cluster of atherosclerotic risk factors that are strongly associated with cardiovascular morbidity and mortality (Lakka et al. 2002; Iwashima et al. 2010). Metabolic syndrome consists of factors including impaired glucose tolerance (IGT) of diabetes, hypertension, hyperlipidaemia and obesity, which may cause widespread microvascular dysfunction and haemodynamic disturbances (Grundy 1999; Wilson et al. 1999). Previous studies have provided conflicting evidence regarding whether components of metabolic syndrome increase or decrease the risk of OAG. The Singapore Malay Eye study (Tan et al. 2009) documented no association between any single or combination of
1
Acta Ophthalmologica 2014
metabolic syndrome components with OAG. In contrast, Newman-Casey et al. (2011) reported an association of OAG with diabetes and hypertension. However, there is little information regarding the associations between NTG and metabolic syndrome. This controversy poses several fundamental questions. Are patients with metabolic syndrome at a greater risk of developing NTG? If metabolic syndrome is associated with NTG, what is the aetiology of this increased risk? These are important issues for ophthalmologists because of significant increases in the incidence of hypertension (Kearney et al. 2005), diabetes, hyperlipidaemia (Wild et al. 2004) and obesity (Parikh et al. 2007) in recent years. The purpose of this study was to determine whether NTG is associated with metabolic syndrome and to evaluate which components of metabolic syndrome are related to NTG.
Methods This study was approved by the Institutional Review Board of the Seoul National University Hospital. This study was designed and conducted in accordance with the tenets of the Declaration of Helsinki. Study population
Individuals were included in the study if they met the following criteria: participation in a glaucoma screening programme at the Gangnam Healthcare Center of Seoul National University Hospital during the period from September 2010 and August 2011 and age of ≥40 years at the time of the examination. The glaucoma screening programme included measurements of IOP and fundus photography. IOP was measured using a non-contact tonometer (model CT10; Topcon Inc., Tokyo, Japan). Fundus photographs were taken using a 45° digital non-mydriatic fundus camera (model EOS D60; Canon Inc., Utsunomiya, Japan). IOP measurements were obtained three times for each eye, and the mean value of these measurements was used for analysis. All data, including age, gender, blood pressure (BP), height, weight, waist circumference measurements, lipid profiles and fasting serum glucose, were collected from subjects’ medical records.
2
Assessment of glaucoma
For glaucoma diagnosis, all participants with findings suggestive of glaucoma such as glaucomatous optic disc appearance or retinal nerve fibre layer (RNFL) defect on colour fundus photography were referred to the glaucoma clinic. Two experienced glaucoma specialists (M.K and J.W.J), who were masked to the subject’s identity, independently evaluated fundus photographs to check for suspicious findings such as glaucomatous optic neuropathy or RNFL defects. The criteria for suspicious findings were as follows: (1) disc suspect – a cup/disc ratio of the optic disc of ≥0.5, cup/disc ratio asymmetry of ≥0.2, rim width at superior position (11 to 1 o’clock) or inferior position (5 to 7 o’clock) of ≤0.2 of the disc diameter, or DH; and/or (2) RNFL suspect – RNFL defects having a width at the disc edge larger than that of a major retinal vessel or diverging in an arcuate or wedge shape; and/or (3) an IOP of ≥22 mmHg. All participants with findings suggestive of glaucoma underwent a further glaucoma evaluation according to the routine referral process of our healthcare centre, including slit-lamp examination, gonioscopy, colour disc photography, red-free RNFL photography (VX-10, Kowa Optimed, Tokyo, Japan) and Swedish interactive thresholding algorithm (SITA standard) 30-2 perimetry (Humphrey field analyzer II, Carl Zeiss Meditec, Dublin, CA, USA). At this stage, IOPs were measured using Goldmann applanation tonometry by a masked glaucoma specialist. Glaucoma evaluation was performed within 3 months after the glaucoma screening programme. NTG diagnosis was made for eyes with all of the following: (1) IOP level below 22 mmHg; (2) normal open anterior chamber angle; (3) the presence of glaucomatous optic nerve head change and corresponding visual field change on automated static perimetry. Glaucomatous visual field defect was defined as (1) outside normal limits on glaucoma hemifield test, (2) three abnormal points, with p < 5% probability of being normal, one with p < 1% by pattern deviation, or (3) pattern standard deviation of 5% confirmed on two consecutive reliable tests
(fixation loss rate ≤20%, false-positive and false-negative error rates ≤25%). The visual field tests were evaluated by a glaucoma specialist in a masked fashion. Definition of metabolic syndrome and hyperlipidaemia
Measurements of height, weight and waist circumference (WC) were obtained for all participants. Body mass index (BMI) was calculated as weight in kilograms divided by height in metres squared. Systolic BP and diastolic BP were measured with an automated sphygmomanometer. Metabolic syndrome was defined by the presence of 3 or more of the following criteria, according to the Regional Office for the Western Pacific Region of the World Health Organization criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guidelines and (WHO/IASO/IOTF 2000; Expert Panel on Detection, Evaluation, & Treatment of High Blood Cholesterol in Adults 2001): (1) abdominal obesity (WC ≥ 90 cm for men or WC ≥ 80 cm for women); (2) hypertriglyceridaemia (triglyceride level ≥ 150 mg/dl); (3) low level of high-density lipoprotein cholesterol (HDL)(HDL < 40 mg/dl in men or HDL < 50 mg/dl in women); (4) hypertension (130/85 mmHg or greater or the use of BP-lowering medication); and (5) IGT (fasting glucose level of 110 mg/dl or greater, or physician diagnosis of diabetes and use of diabetes medication). Diabetes was defined as a fasting plasma glucose level of 126 mg/dl or greater on at least two occasions, plasma glucose of 200 mg/dl or greater 2 hr after a 75-g oral glucose tolerance test, requirement of insulin or glucoselowering medication to control glucose levels or a medical history of dietcontrolled diabetes. In this study, hyperlipidaemia was defined as total serum cholesterol >220 mg/dl or a calculated value of low-density cholesterol >140 mg/dl, according to Japan Atherosclerosis Society guidelines (Hata et al. 2002). Analyses
In this study, subjects were divided into two groups according to presence of NTG; subjects with NTG (NTG
Acta Ophthalmologica 2014
group) and without NTG (control group). Thus, the control group included patients with metabolic syndrome, but not NTG. The two groups were compared using unpaired t-test and chi-square test. Statistical analyses were performed with SAS, version 9.1 software packages (SAS Institute, Cary, NC, USA). The results were considered statistically significant when the p value was
Metabolic syndrome as a risk factor in normal-tension glaucoma Mijin Kim,1,2 Jin Wook Jeoung,1,2 Ki Ho Park,1,2 Won Hyuck Oh,3 Hyuk Jin Choi1,4 and Dong Myung Kim1,2 1
Department Department 3 Department 4 Department 2
of of of of
Ophthalmology, Ophthalmology, Ophthalmology, Ophthalmology,
Seoul National University College of Medicine, Seoul, Korea Seoul National University Hospital, Seoul, Korea Inje University Sanggye Paik Hospital, Seoul, Korea Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea
ABSTRACT. Purpose: To determine whether normal-tension glaucoma (NTG) is associated with metabolic syndrome and to evaluate which components of metabolic syndrome are related to NTG. Methods: This study included 18240 participants who underwent health check-ups including fundus photography and intraocular pressure measurements. For NTG diagnosis, all participants with findings suggestive of glaucoma completed a further glaucoma evaluation, including applanation tonometry, gonioscopy and standard automated perimetry. The National Cholesterol Education Program Adult Treatment Panel III guideline was used to characterize metabolic syndrome. Results: Of the 18240 participants, 3635 (19.9%) had metabolic syndrome and 300 (1.6%) were diagnosed with NTG. The prevalence of NTG was 1.5% in subjects without metabolic syndrome and 2.1% in subjects with metabolic syndrome. The presence of metabolic syndrome was not significantly associated with NTG (p = 0.067). There were significant associations of NTG with hypertension and impaired glucose tolerance (IGT) among the individual components of metabolic syndrome (OR, 1.53; 95% CI, 1.20–1.94; p = 0.001 and OR, 1.47; 95% CI, 1.12–1.94; p = 0.006). NTG was positively associated with the number of metabolic syndrome components (OR, 1.10; p = 0.040). Multivariable analysis showed the prevalence of NTG to be significantly higher in participants aged between 50 and 70 years relative to those aged 40 to 50 years, male gender, participants with higher baseline intraocular pressure, hypertension and IGT. Conclusions: Of the metabolic syndrome components, hypertension and IGT contributed to an increased risk of NTG. These findings suggest that metabolic syndrome components may play a role in the pathogenesis of NTG. Key words: diabetes – hypertension – metabolic syndrome – normal-tension glaucoma
Acta Ophthalmol. ª 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
doi: 10.1111/aos.12434 This study was supported by a grant of the Korea Health technology R&D Project, Ministry of Health & Welfare, Republic of Korea [Grant No: A121615 and A101310].
Introduction Normal-tension glaucoma (NTG), a subset of open-angle glaucoma
(OAG), is an entity with progressive glaucomatous optic neuropathy and corresponding visual field defects, but
with intraocular pressure (IOP) within the statistically normal range (Shields 2008). Because patients with NTG have normal IOP, vascular abnormalities such as vasospasms or ischaemia are thought to play an important role in the pathogenesis of NTG (Caprioli & Spaeth 1984). Disc haemorrhage (DH), which is more frequently observed in patients with NTG than in patients with high-tension glaucoma, is suggested to be a consequence of hemodynamic disturbances, including ischaemic microinfarction in the optic nerve head (Begg et al. 1971), disorders of retinal circulation (Sonnsjo & Krakau 1993), decrease in capillary perfusion (Kurvinen et al. 2010) and primary vascular dysregulation (Grieshaber et al. 2006), although the pathogenesis of DH is not yet fully understood. Metabolic syndrome is a cluster of atherosclerotic risk factors that are strongly associated with cardiovascular morbidity and mortality (Lakka et al. 2002; Iwashima et al. 2010). Metabolic syndrome consists of factors including impaired glucose tolerance (IGT) of diabetes, hypertension, hyperlipidaemia and obesity, which may cause widespread microvascular dysfunction and haemodynamic disturbances (Grundy 1999; Wilson et al. 1999). Previous studies have provided conflicting evidence regarding whether components of metabolic syndrome increase or decrease the risk of OAG. The Singapore Malay Eye study (Tan et al. 2009) documented no association between any single or combination of
1
Acta Ophthalmologica 2014
metabolic syndrome components with OAG. In contrast, Newman-Casey et al. (2011) reported an association of OAG with diabetes and hypertension. However, there is little information regarding the associations between NTG and metabolic syndrome. This controversy poses several fundamental questions. Are patients with metabolic syndrome at a greater risk of developing NTG? If metabolic syndrome is associated with NTG, what is the aetiology of this increased risk? These are important issues for ophthalmologists because of significant increases in the incidence of hypertension (Kearney et al. 2005), diabetes, hyperlipidaemia (Wild et al. 2004) and obesity (Parikh et al. 2007) in recent years. The purpose of this study was to determine whether NTG is associated with metabolic syndrome and to evaluate which components of metabolic syndrome are related to NTG.
Methods This study was approved by the Institutional Review Board of the Seoul National University Hospital. This study was designed and conducted in accordance with the tenets of the Declaration of Helsinki. Study population
Individuals were included in the study if they met the following criteria: participation in a glaucoma screening programme at the Gangnam Healthcare Center of Seoul National University Hospital during the period from September 2010 and August 2011 and age of ≥40 years at the time of the examination. The glaucoma screening programme included measurements of IOP and fundus photography. IOP was measured using a non-contact tonometer (model CT10; Topcon Inc., Tokyo, Japan). Fundus photographs were taken using a 45° digital non-mydriatic fundus camera (model EOS D60; Canon Inc., Utsunomiya, Japan). IOP measurements were obtained three times for each eye, and the mean value of these measurements was used for analysis. All data, including age, gender, blood pressure (BP), height, weight, waist circumference measurements, lipid profiles and fasting serum glucose, were collected from subjects’ medical records.
2
Assessment of glaucoma
For glaucoma diagnosis, all participants with findings suggestive of glaucoma such as glaucomatous optic disc appearance or retinal nerve fibre layer (RNFL) defect on colour fundus photography were referred to the glaucoma clinic. Two experienced glaucoma specialists (M.K and J.W.J), who were masked to the subject’s identity, independently evaluated fundus photographs to check for suspicious findings such as glaucomatous optic neuropathy or RNFL defects. The criteria for suspicious findings were as follows: (1) disc suspect – a cup/disc ratio of the optic disc of ≥0.5, cup/disc ratio asymmetry of ≥0.2, rim width at superior position (11 to 1 o’clock) or inferior position (5 to 7 o’clock) of ≤0.2 of the disc diameter, or DH; and/or (2) RNFL suspect – RNFL defects having a width at the disc edge larger than that of a major retinal vessel or diverging in an arcuate or wedge shape; and/or (3) an IOP of ≥22 mmHg. All participants with findings suggestive of glaucoma underwent a further glaucoma evaluation according to the routine referral process of our healthcare centre, including slit-lamp examination, gonioscopy, colour disc photography, red-free RNFL photography (VX-10, Kowa Optimed, Tokyo, Japan) and Swedish interactive thresholding algorithm (SITA standard) 30-2 perimetry (Humphrey field analyzer II, Carl Zeiss Meditec, Dublin, CA, USA). At this stage, IOPs were measured using Goldmann applanation tonometry by a masked glaucoma specialist. Glaucoma evaluation was performed within 3 months after the glaucoma screening programme. NTG diagnosis was made for eyes with all of the following: (1) IOP level below 22 mmHg; (2) normal open anterior chamber angle; (3) the presence of glaucomatous optic nerve head change and corresponding visual field change on automated static perimetry. Glaucomatous visual field defect was defined as (1) outside normal limits on glaucoma hemifield test, (2) three abnormal points, with p < 5% probability of being normal, one with p < 1% by pattern deviation, or (3) pattern standard deviation of 5% confirmed on two consecutive reliable tests
(fixation loss rate ≤20%, false-positive and false-negative error rates ≤25%). The visual field tests were evaluated by a glaucoma specialist in a masked fashion. Definition of metabolic syndrome and hyperlipidaemia
Measurements of height, weight and waist circumference (WC) were obtained for all participants. Body mass index (BMI) was calculated as weight in kilograms divided by height in metres squared. Systolic BP and diastolic BP were measured with an automated sphygmomanometer. Metabolic syndrome was defined by the presence of 3 or more of the following criteria, according to the Regional Office for the Western Pacific Region of the World Health Organization criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guidelines and (WHO/IASO/IOTF 2000; Expert Panel on Detection, Evaluation, & Treatment of High Blood Cholesterol in Adults 2001): (1) abdominal obesity (WC ≥ 90 cm for men or WC ≥ 80 cm for women); (2) hypertriglyceridaemia (triglyceride level ≥ 150 mg/dl); (3) low level of high-density lipoprotein cholesterol (HDL)(HDL < 40 mg/dl in men or HDL < 50 mg/dl in women); (4) hypertension (130/85 mmHg or greater or the use of BP-lowering medication); and (5) IGT (fasting glucose level of 110 mg/dl or greater, or physician diagnosis of diabetes and use of diabetes medication). Diabetes was defined as a fasting plasma glucose level of 126 mg/dl or greater on at least two occasions, plasma glucose of 200 mg/dl or greater 2 hr after a 75-g oral glucose tolerance test, requirement of insulin or glucoselowering medication to control glucose levels or a medical history of dietcontrolled diabetes. In this study, hyperlipidaemia was defined as total serum cholesterol >220 mg/dl or a calculated value of low-density cholesterol >140 mg/dl, according to Japan Atherosclerosis Society guidelines (Hata et al. 2002). Analyses
In this study, subjects were divided into two groups according to presence of NTG; subjects with NTG (NTG
Acta Ophthalmologica 2014
group) and without NTG (control group). Thus, the control group included patients with metabolic syndrome, but not NTG. The two groups were compared using unpaired t-test and chi-square test. Statistical analyses were performed with SAS, version 9.1 software packages (SAS Institute, Cary, NC, USA). The results were considered statistically significant when the p value was
