Clinical and Epidemiologic Research
Epidemiological Association Between Systemic Diseases and Age-Related Macular Degeneration: The Korea National Health and Nutrition Examination Survey 2008– 2011 Bum-Joo Cho,1,2 Jang Won Heo,1,2 Jae Pil Shin,3 Jeeyun Ahn,1,4 Tae Wan Kim,1,4 and Hum Chung1,2 1
Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea Department of Ophthalmology, Seoul National University Hospital, Seoul, Korea 3 Department of Ophthalmology, Kyungpook National University School of Medicine, Daegu, Korea 4Department of Ophthalmology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea 2
Correspondence: Jang Won Heo, Department of Ophthalmology, Seoul National University College of Medicine, 101 Daehang-no, Jongnogu, Seoul 110-744, Korea; [email protected] Submitted: March 17, 2014 Accepted: June 12, 2014 Citation: Cho B-J, Heo JW, Shin JP, Ahn J, Kim TW, Chung H. Epidemiological association between systemic diseases and age-related macular degeneration: the Korea National Health and Nutrition Examination Survey 2008–2011. Invest Ophthalmol Vis Sci. 2014;55:4430–4437. DOI:10.1167/ iovs.14-14379
PURPOSE. We examined the epidemiological association between systemic diseases and agerelated macular degeneration (AMD) in the general Korean population. METHODS. This cross-sectional study involved nationally representative data obtained from the 2008 to 2011 Korea National Health and Nutrition Examination Surveys. A total of 14,352 subjects aged ‡40 years participated in standardized health interviews regarding physiciandiagnosis of several systemic diseases as well as physical examinations, including fundus photography for the evaluation of AMD. RESULTS. The overall prevalence rates of early, late, and any AMD were 6.0%, 0.6%, and 6.6%, respectively. In univariate logistic regression analyses adjusted for age and sex as well as smoking in late AMD, any AMD and late AMD were less prevalent among diabetic patients and more prevalent in participants with a history of liver cancer. A history of liver cirrhosis was associated with a higher prevalence of any AMD. In the final multivariate model, the associated factors for any AMD included age (odds ratio [OR], 1.09), the presence of diabetes mellitus (DM; OR, 0.74), and a history of liver cancer (OR, 4.32). Factors associated with late AMD included age (OR, 1.09), ever-smoking history (OR, 2.45), the presence of DM (OR, 0.22), and a history of liver cancer (OR, 12.51). The presence of diabetic retinopathy was associated with a lower prevalence of any AMD (OR, 0.35). CONCLUSIONS. When adjusted for confounders, any AMD and late AMD were less prevalent in diabetic patients. In contrast, a history of liver cancer was associated with a higher prevalence of any AMD and late AMD. Keywords: age-related macular degeneration, risk factor, diabetes mellitus, liver cancer
ge-related macular degeneration (AMD) is the leading cause of visual impairment among the elderly population in developed countries.1,2 The pathophysiology of AMD is yet to be unraveled, but several risk factors for the development of AMD have been identified, including smoking, hyperopia, and genetic variation in complement factor H.3–5 Revealing risk factors will provide valuable information to better understand AMD pathogenesis. Among systemic diseases, several medical conditions occasionally have been associated with risk of AMD.6,7 Epidemiological studies have reported hypertension, some cardiovascular diseases, and diabetes mellitus (DM) to be associated with increased AMD prevalence7–9 However, other studies have shown inconsistent results for these diseases,4,10 and have even reported an inverse association of DM with AMD.11 The association of other systemic diseases with AMD remains undisclosed due to insufficient data. Unveiling the relationship between systemic diseases and AMD would
contribute to increased understanding of the pathophysiology of AMD, allow screening of patients at risk, and ultimately may help prevent AMD. In the present study, we investigated the association between various systemic diseases and AMD in the Korean general population. To acquire a nationally representative sample, we used data obtained from the Korea National Health and Nutrition Examination Survey (KNHANES) on behalf of the Korean Ophthalmological Society (KOS). The ethnic homogeneity of Korea is advantageous in identifying disease risk factors, because it would minimize bias resulting from interracial differences.12 Consequently, several systemic diseases including cardiovascular, endocrinologic, pulmonary, and arthritic diseases, as well as malignancy, were examined for association with AMD in a large-numbered study population. To our knowledge, this is the first comprehensive study on this association in Asian ethnics.
Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc. www.iovs.org j ISSN: 1552-5783
4430
A
IOVS j July 2014 j Vol. 55 j No. 7 j 4431
Association Between Systemic Diseases and AMD
METHODS Study Population The data analyzed in this study were acquired from the fourth and fifth KNHANES performed from July 2008 to December 2011. The KNHANES is an ongoing nationwide cross-sectional survey that examines the health and nutritional status of the noninstitutionalized civilian South Korean population.13 The survey has been conducted annually since 2007 by the Korea Center for Disease Control and Prevention (KCDC), and ophthalmologic examination was included beginning in the second half of 2008. Details of the KNHANES design and methodology have been described previously.12,13 To summarize briefly, the KNHANES includes approximately 4000 households annually based on national census data, using a stratified multistage cluster sampling method, which ensured that annual survey results represented the general Korean population and that the results from each year could be merged.12 All family members aged ‡1 year in the sampled households were included as eligible subjects. The study described here adhered to the tenets of the Declaration of Helsinki, and written informed consent was obtained from all participants. The survey protocol was approved by the Institutional Review Board (IRB) of the KCDC (IRB No. 200804EXP-01-C, 2009-01CON-03-2C, 2010-02CON-21-C, 201102CON-06-C). Subjects were asked to participate in health interviews and examinations performed by trained teams in mobile centers. Demographic variables, current and past medical conditions, and health behavior patterns were obtained using detailed standardized questionnaires in health interview surveys. Physical examinations involved body profile measurement, blood tests, routine urinalysis, and ophthalmologic examinations, including a visual acuity test, applanation tonometry, and slit-lamp biomicroscopy. A 458 nonmydriatic color fundus photograph was taken for each eye in all participants aged ‡19 years using a digital fundus camera (TRC-NW6S; Topcon, Tokyo, Japan). If the participant had a history of DM, random blood glucose level ‡200 mg/dL, or suspected diabetic retinopathy (DR) in the nonmydriatic fundus photograph, seven standard fundus photographs were taken according to the Early Treatment for Diabetic Retinopathy Study (ETDRS) protocol after pharmacologic pupillary dilatation. Ultimately, participants ‡40 years of age with ‡1 evaluable fundus photographs were included in this study.
Evaluation of Systemic Diseases The status of various systemic diseases was investigated using self-reported questionnaires regarding physician diagnosis in health interview surveys. Study participants were asked twice about systemic disease status: once for the existence of the disease and once for physician confirmation of the diagnosis. For example, the first question for stroke was, ‘‘Have you ever suffered from stroke?’’ The second question was, ‘‘Was the diagnosis of stroke confirmed by a doctor?’’ Only participants who answered in the affirmative to both questions were considered to have the systemic disease. Nonspecific diseases, such as ‘‘thyroid disease’’ or ‘‘dyslipidemia’’ were excluded from analyses in this study. In cases of DM and hypertension, multiple diagnostic criteria were combined to evaluate the disease status. The presence of DM was defined by any of the following criteria: a self-reported history of physician-diagnosed DM, a self-reported history of DM and current treatment for DM using insulin or oral hypoglycemic agent, and a fasting plasma glucose level
measured by blood test of ‡126 mg/dL (7.0 mmol/L). Hypertension was defined by either a self-reported history of hypertension diagnosis and current usage of antihypertensive drugs, or a corrected measured systolic blood pressure of ‡140 mm Hg or corrected measured diastolic blood pressure of ‡90 mm Hg.
Evaluation of AMD and DR Each fundus image was graded twice for the presence and type of AMD. Preliminary grading was done onsite by ophthalmologists trained by the National Epidemiologic Survey Committee of the KOS using the International Age-related Maculopathy Epidemiological Study Group grading system.12,14 Nine retinal specialists with expertise in the grading of AMD, who were masked to the patients’ characteristics, performed detailed grading for their own image subsets mutually exclusive of one another. An independent specialist (JPS) resolved any discrepancies between the preliminary and detailed grading. The presence of any AMD was defined as having either early AMD or late AMD. When one eye was not assessable, the subject was assigned the grade of the other eye. When the severity of AMD differed between both eyes, the subject was assigned the more advanced grade. The quality of grading was verified by the KOS. Grading agreement between the preliminary graders and the standard reading specialists ranged from 90.2% to 95.3%. In addition, the presence of DR among diabetic patients was evaluated in seven mydriatic standard fundus photographs according to the ETDRS protocol and was analyzed for association with AMD.
Statistical Analysis All estimates were acquired using sample weights adjusted for response rate, extraction rate, and distribution in the Korean population. Continuous variables were expressed as mean 6 SE or mean with 95% confidence intervals (CIs). Categorical and continuous variables were examined using odds ratios (ORs) with 95% CIs. Before main analyses, the covariates for the presence of any and late AMD were identified by age- and sex-adjusted univariate logistic regression analyses among demographic risk factors and health-behavioral variables. Next, after adjusting for age, sex, and identified covariates, univariate logistic regression analysis was performed for each systemic disease to select candidate diseases with a threshold P value of
Epidemiological Association Between Systemic Diseases and Age-Related Macular Degeneration: The Korea National Health and Nutrition Examination Survey 2008– 2011 Bum-Joo Cho,1,2 Jang Won Heo,1,2 Jae Pil Shin,3 Jeeyun Ahn,1,4 Tae Wan Kim,1,4 and Hum Chung1,2 1
Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea Department of Ophthalmology, Seoul National University Hospital, Seoul, Korea 3 Department of Ophthalmology, Kyungpook National University School of Medicine, Daegu, Korea 4Department of Ophthalmology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea 2
Correspondence: Jang Won Heo, Department of Ophthalmology, Seoul National University College of Medicine, 101 Daehang-no, Jongnogu, Seoul 110-744, Korea; [email protected] Submitted: March 17, 2014 Accepted: June 12, 2014 Citation: Cho B-J, Heo JW, Shin JP, Ahn J, Kim TW, Chung H. Epidemiological association between systemic diseases and age-related macular degeneration: the Korea National Health and Nutrition Examination Survey 2008–2011. Invest Ophthalmol Vis Sci. 2014;55:4430–4437. DOI:10.1167/ iovs.14-14379
PURPOSE. We examined the epidemiological association between systemic diseases and agerelated macular degeneration (AMD) in the general Korean population. METHODS. This cross-sectional study involved nationally representative data obtained from the 2008 to 2011 Korea National Health and Nutrition Examination Surveys. A total of 14,352 subjects aged ‡40 years participated in standardized health interviews regarding physiciandiagnosis of several systemic diseases as well as physical examinations, including fundus photography for the evaluation of AMD. RESULTS. The overall prevalence rates of early, late, and any AMD were 6.0%, 0.6%, and 6.6%, respectively. In univariate logistic regression analyses adjusted for age and sex as well as smoking in late AMD, any AMD and late AMD were less prevalent among diabetic patients and more prevalent in participants with a history of liver cancer. A history of liver cirrhosis was associated with a higher prevalence of any AMD. In the final multivariate model, the associated factors for any AMD included age (odds ratio [OR], 1.09), the presence of diabetes mellitus (DM; OR, 0.74), and a history of liver cancer (OR, 4.32). Factors associated with late AMD included age (OR, 1.09), ever-smoking history (OR, 2.45), the presence of DM (OR, 0.22), and a history of liver cancer (OR, 12.51). The presence of diabetic retinopathy was associated with a lower prevalence of any AMD (OR, 0.35). CONCLUSIONS. When adjusted for confounders, any AMD and late AMD were less prevalent in diabetic patients. In contrast, a history of liver cancer was associated with a higher prevalence of any AMD and late AMD. Keywords: age-related macular degeneration, risk factor, diabetes mellitus, liver cancer
ge-related macular degeneration (AMD) is the leading cause of visual impairment among the elderly population in developed countries.1,2 The pathophysiology of AMD is yet to be unraveled, but several risk factors for the development of AMD have been identified, including smoking, hyperopia, and genetic variation in complement factor H.3–5 Revealing risk factors will provide valuable information to better understand AMD pathogenesis. Among systemic diseases, several medical conditions occasionally have been associated with risk of AMD.6,7 Epidemiological studies have reported hypertension, some cardiovascular diseases, and diabetes mellitus (DM) to be associated with increased AMD prevalence7–9 However, other studies have shown inconsistent results for these diseases,4,10 and have even reported an inverse association of DM with AMD.11 The association of other systemic diseases with AMD remains undisclosed due to insufficient data. Unveiling the relationship between systemic diseases and AMD would
contribute to increased understanding of the pathophysiology of AMD, allow screening of patients at risk, and ultimately may help prevent AMD. In the present study, we investigated the association between various systemic diseases and AMD in the Korean general population. To acquire a nationally representative sample, we used data obtained from the Korea National Health and Nutrition Examination Survey (KNHANES) on behalf of the Korean Ophthalmological Society (KOS). The ethnic homogeneity of Korea is advantageous in identifying disease risk factors, because it would minimize bias resulting from interracial differences.12 Consequently, several systemic diseases including cardiovascular, endocrinologic, pulmonary, and arthritic diseases, as well as malignancy, were examined for association with AMD in a large-numbered study population. To our knowledge, this is the first comprehensive study on this association in Asian ethnics.
Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc. www.iovs.org j ISSN: 1552-5783
4430
A
IOVS j July 2014 j Vol. 55 j No. 7 j 4431
Association Between Systemic Diseases and AMD
METHODS Study Population The data analyzed in this study were acquired from the fourth and fifth KNHANES performed from July 2008 to December 2011. The KNHANES is an ongoing nationwide cross-sectional survey that examines the health and nutritional status of the noninstitutionalized civilian South Korean population.13 The survey has been conducted annually since 2007 by the Korea Center for Disease Control and Prevention (KCDC), and ophthalmologic examination was included beginning in the second half of 2008. Details of the KNHANES design and methodology have been described previously.12,13 To summarize briefly, the KNHANES includes approximately 4000 households annually based on national census data, using a stratified multistage cluster sampling method, which ensured that annual survey results represented the general Korean population and that the results from each year could be merged.12 All family members aged ‡1 year in the sampled households were included as eligible subjects. The study described here adhered to the tenets of the Declaration of Helsinki, and written informed consent was obtained from all participants. The survey protocol was approved by the Institutional Review Board (IRB) of the KCDC (IRB No. 200804EXP-01-C, 2009-01CON-03-2C, 2010-02CON-21-C, 201102CON-06-C). Subjects were asked to participate in health interviews and examinations performed by trained teams in mobile centers. Demographic variables, current and past medical conditions, and health behavior patterns were obtained using detailed standardized questionnaires in health interview surveys. Physical examinations involved body profile measurement, blood tests, routine urinalysis, and ophthalmologic examinations, including a visual acuity test, applanation tonometry, and slit-lamp biomicroscopy. A 458 nonmydriatic color fundus photograph was taken for each eye in all participants aged ‡19 years using a digital fundus camera (TRC-NW6S; Topcon, Tokyo, Japan). If the participant had a history of DM, random blood glucose level ‡200 mg/dL, or suspected diabetic retinopathy (DR) in the nonmydriatic fundus photograph, seven standard fundus photographs were taken according to the Early Treatment for Diabetic Retinopathy Study (ETDRS) protocol after pharmacologic pupillary dilatation. Ultimately, participants ‡40 years of age with ‡1 evaluable fundus photographs were included in this study.
Evaluation of Systemic Diseases The status of various systemic diseases was investigated using self-reported questionnaires regarding physician diagnosis in health interview surveys. Study participants were asked twice about systemic disease status: once for the existence of the disease and once for physician confirmation of the diagnosis. For example, the first question for stroke was, ‘‘Have you ever suffered from stroke?’’ The second question was, ‘‘Was the diagnosis of stroke confirmed by a doctor?’’ Only participants who answered in the affirmative to both questions were considered to have the systemic disease. Nonspecific diseases, such as ‘‘thyroid disease’’ or ‘‘dyslipidemia’’ were excluded from analyses in this study. In cases of DM and hypertension, multiple diagnostic criteria were combined to evaluate the disease status. The presence of DM was defined by any of the following criteria: a self-reported history of physician-diagnosed DM, a self-reported history of DM and current treatment for DM using insulin or oral hypoglycemic agent, and a fasting plasma glucose level
measured by blood test of ‡126 mg/dL (7.0 mmol/L). Hypertension was defined by either a self-reported history of hypertension diagnosis and current usage of antihypertensive drugs, or a corrected measured systolic blood pressure of ‡140 mm Hg or corrected measured diastolic blood pressure of ‡90 mm Hg.
Evaluation of AMD and DR Each fundus image was graded twice for the presence and type of AMD. Preliminary grading was done onsite by ophthalmologists trained by the National Epidemiologic Survey Committee of the KOS using the International Age-related Maculopathy Epidemiological Study Group grading system.12,14 Nine retinal specialists with expertise in the grading of AMD, who were masked to the patients’ characteristics, performed detailed grading for their own image subsets mutually exclusive of one another. An independent specialist (JPS) resolved any discrepancies between the preliminary and detailed grading. The presence of any AMD was defined as having either early AMD or late AMD. When one eye was not assessable, the subject was assigned the grade of the other eye. When the severity of AMD differed between both eyes, the subject was assigned the more advanced grade. The quality of grading was verified by the KOS. Grading agreement between the preliminary graders and the standard reading specialists ranged from 90.2% to 95.3%. In addition, the presence of DR among diabetic patients was evaluated in seven mydriatic standard fundus photographs according to the ETDRS protocol and was analyzed for association with AMD.
Statistical Analysis All estimates were acquired using sample weights adjusted for response rate, extraction rate, and distribution in the Korean population. Continuous variables were expressed as mean 6 SE or mean with 95% confidence intervals (CIs). Categorical and continuous variables were examined using odds ratios (ORs) with 95% CIs. Before main analyses, the covariates for the presence of any and late AMD were identified by age- and sex-adjusted univariate logistic regression analyses among demographic risk factors and health-behavioral variables. Next, after adjusting for age, sex, and identified covariates, univariate logistic regression analysis was performed for each systemic disease to select candidate diseases with a threshold P value of
