The authors have declared that no competing interests exist.
Nonalcoholic fatty liver disease (NAFLD), an emerging multisystem disease, has the similar pathogenesis with diabetes and is prevalent in diabetes. This study investigated whether NAFLD is associated with retinopathy in individuals with diabetes and without diabetes.
The association between NAFLD and retinopathy was investigated in 5963 participants aged 40 years and older who participated in the NHANES III, a nationally representative, population-based and cross-sectional study. NAFLD was detected via ultrasonography, and fundus photographs were obtained to grade retinopathy patterns. We performed multivariate logistic regression analysis to investigate the relationship between the presence of retinopathy and NAFLD and diabetes.
After adjusting for multiple covariates, NAFLD population had no evidence of retinopathy increase in population without diabetes (odds ratio [OR]: 0.77; 95% confidence interval [CI]: 0.48 to 1.26). In addition, NAFLD in individuals with diabetes was not significantly associated with retinopathy (OR: 0.77; 95% CI: 0.47 to 1.26), independent of age, gender, ethnicity, waist circumference, serum high-density lipoprotein (HDL) cholesterol, serum triglycerides, systolic blood pressure, and glycated hemoglobin.
In the US general population, NAFLD is not a precipitating factor of retinopathy in population with or without diabetes.
Retinopathy is a type of retinal microvasculature disease and a well-known complication of diabetes and hypertension[
The NHANES III was conducted by the Centers for Disease Control and Prevention using a nationwide probability sample of the United States non-institutionalized civilian population from 1988 to 1994[
An examiner at the MEC photographed the ocular fundus of a randomly selected eye in participants aged over 40 years. One non-stereoscopic, color, 45-degree photograph centered between the optic nerve and macula was obtained with a film-based Canon CR4–45NM non-mydriatic fundus camera (Canon USA, Lake Success, New York, USA). If an extremely small pupil, severe corneal or lens opacity, complete retinal detachment, or other prohibitive factors were observed in the randomly selected eye, the other eye was photographed. No photograph was obtained if neither eye was suitable.
The presence of DR, age-related maculopathy, and other retinal diseases was assessed using the fundus images by photograph graders from the University of Wisconsin-Madison, Department of Ophthalmology. Retinopathy was defined as the presence of the following factors on the fundus photograph: retinal microaneurysms only (level 20); hemorrhages, soft exudates, hard exudates, or intraretinal microvascular abnormalities (IRMAs) without microaneurysms (levels 14 and 15); non-proliferative DR (levels 31, 41, and 51); proliferative DR (levels 60, 65, and 70); or non-DR (level 12).
Participants underwent a gallbladder ultrasound in NHANES III program. A hepatic steatosis examination was conducted to assess the presence of fat within the hepatic parenchyma. The archived original gallbladder ultrasonography videotapes and NHANES III results observed during the MEC examination were reviewed.
Hepatic steatosis was evaluated using the following five criteria: parenchymal brightness, liver to kidney contrast, deep beam attenuation, bright vessel walls, and gallbladder wall definition. The presence, absence, or degree of these five criteria was recorded. An experienced radiologist supervised the trained ultrasound image readers. Aside from normal sonography patterns, the degree of hepatic steatosis severity was classified as mild, moderate, or severe.
Diabetes was defined as a fasting plasma glucose level ≥126 mg/dL, glycated hemoglobin level ≥6.5%, diabetes history, or hypoglycemia medication use. A trained research assistant measured blood pressure. Waist circumference was measured by a steel measuring tape at the iliac crest from the right side of the body. Serum HDL cholesterol, triglycerides, and glycated hemoglobin were measured via chemical analyses (Hitachi 737 Analyzer; Indianapolis, Indiana)
We classified the participants into four groups as follows: group 1, no diabetes mellitus (DM) or NAFLD; group 2, only NAFLD; group 3, only DM; and group 4, both DM and NAFLD. Retinopathy was considered as present or absent. The baseline characteristics of the participants were compared with a Pearson chi-square test for categorical variables or and ANOVA or Kruskal-Wallis test for continuous variables.
Multivariate logistic regression analysis was also performed to assess associations between the four groups and retinopathy. In addition, group 1 was considered as a reference group. Models were adjusted for demographic factors as follows: model 1 was adjusted for age; model 2 was additionally adjusted for gender and ethnicity; and model 3 was adjusted for waist circumference, serum HDL cholesterol, serum triglycerides, systolic blood pressure, and glycated hemoglobin.
Additional analyses were conducted in groups 3 and 4. For these analyses, group 3 was considered the reference group and the relationships between the two groups and retinopathy were investigated by multivariate logistic regression analysis. This analysis was also adjusted for the demographic factors included in models 1, 2, and 3. Moreover, the fundus patterns based on the NHANES III classification were compared between the two groups without diabetes. A p-value<0.05 was considered statistically significant. All analyses were performed using SPSS (Version 18.0 for Windows, SPSS, Inc., Chicago, IL, USA) and utilized the sample weights and design effects of the survey.
The numbers of participants in the four groups were as follows: group 1 (n = 3807), group 2 (n = 1211), group 3 (n = 486), and group 4 (n = 459) (
Group | |||||
---|---|---|---|---|---|
Characteristic | Total Population (n = 5963) | DM(-)& NAFLD(-) (n = 3807) | DM(-)& NAFLD(+) (n = 1211) | DM(+)& NAFLD(-) (n = 486) | DM(+)& NAFLD(+) (n = 459) |
Age (years) | 54.03 ± 0.32 | 53.37± 0.35 | 54.27±0.39 | 57.77±0.66 | 58.11±0.80 |
Male (%) | 46.2±0.8 | 43.7±0.9 | 54.7±1.5 | 43.4±3.5 | 48.5±4.2 |
Ethnicity (%) | |||||
Non-Hispanic white | 80.8±1.3 | 82.2±1.3 | 81.5±1.8 | 66.1±3.7 | 73.9±2.9 |
Systolic blood pressure (mmHg) | 126.36±0.41 | 124.18±0.44 | 130.04±0.91 | 132.21±1.36 | 135.57±1.14 |
Waist circumference (cm) | 95.74±0.33 | 91.91±0.29 | 104.08±0.58 | 101.35±1.11 | 109.38±1.05 |
Serum HDL cholesterol (mg/dL) | 50.39±0.42 | 52.63±0.47 | 45.18±0.74 | 47.03±1.07 | 43.34±1.26 |
Serum triglycerides (mg/dL) | 161.85±3.19 | 136.22±2.20 | 210.64±6.63 | 215.68±29.14 | 265.86±14.53 |
Glycated hemoglobin (%) | 5.56±0.03 | 5.32±0.02 | 5.39±0.02 | 7.37±0.18 | 7.77±0.16 |
Retinopathy (%) | 5.3±0.5 | 3.6±0.6 | 3.5±0.7 | 21.9±3.9 | 19.1±2.2 |
Data are presented as the means ± standard errors or percentages ± standard errors.
DM: diabetes mellitus
NAFLD: nonalcoholic fatty liver disease
HDL: high density lipoprotein
In the multivariate logistic regression analysis, retinopathy was significantly associated with the diabetes groups compared with group 1 (group 3: odds ratio [OR]: 3.84, 95% confidence interval [CI]: 2.50–5.92; group 4: OR: 2.66, 95% CI: 1.44–4.90) after adjusting for age, gender, ethnicity, waist circumference, serum HDL cholesterol, serum triglycerides, systolic blood pressure, and glycated hemoglobin (
Group | ||||
---|---|---|---|---|
DM(-)& NAFLD(-) | DM(-)& NAFLD(+) | DM(+)& NAFLD(-) | DM(+)& NAFLD(+) | |
Unadjusted | 1 | 0.97(0.58–1.63) | 7.53(4.66–12.16) | 6.33(3.89–10.31) |
Model 1 | 1 | 0.96(0.57–1.60) | 7.07(4.26–11.73) | 5.91(3.55–9.85) |
Model 2 | 1 | 0.94(0.56–1.56) | 7.07(4.15–12.05) | 5.86(3.53–9.74) |
Model 3 | 1 | 0.77(0.48–1.26) | 3.84(2.50–5.92) | 2.66(1.44–4.90) |
Data are presented as odds ratios (95% confidence intervals)
DM: diabetes mellitus
NAFLD: nonalcoholic fatty liver disease
Model 1: adjusted for age
Model 2: adjusted for age, gender, and race-ethnicity
Model 3: adjusted for age, gender, race-ethnicity, waist circumference, serum HDL cholesterol, serum triglycerides, systolic blood pressure, and glycated hemoglobin
Group | |||
---|---|---|---|
DM(+)& NAFLD(-) | DM(+)& NAFLD(+) | P | |
Unadjusted | 1 | 0.84(0.57–1.23) | 0.369 |
Model 1 | 1 | 0.84(0.57–1.24) | 0.368 |
Model 2 | 1 | 0.84(0.56–1.24) | 0.359 |
Model 3 | 1 | 0.77(0.47–1.26) | 0.284 |
Data are presented as odds ratios (95% confidence intervals)
DM: diabetes mellitus
NAFLD: nonalcoholic fatty liver disease
Model 1: adjusted for age
Model 2: adjusted for age, gender, and race-ethnicity
Model 3: adjusted for age, gender, race-ethnicity, waist circumference, serum HDL cholesterol, serum triglycerides, systolic blood pressure, and glycated hemoglobin
The characteristics of the fundus photographs stratified by retinopathy status are shown in
Retinopathy Lesion | DM(-)& NAFLD(-) | DM(-)& NAFLD(+) | DM(+)& NAFLD(-) | DM(+)& NAFLD(+) |
---|---|---|---|---|
MA only | 61.1 | 65.8 | 40.9 | 30.5 |
Hemorrhage, hard/soft exudates, IRMA without MA | 20.8 | 15.6 | 8.8 | 15.1 |
Nonproliferative retinopathy | 10.5 | 12.1 | 44.9 | 45.4 |
Nondiabetic retinopathy | 7.6 | 6.5 | 2.3 | 4.8 |
Proliferative retinopathy | 0 | 0 | 3.1 | 4.2 |
IRMA: intraretinal microvascular abnormalities
MA: microaneurysms
DM: diabetes mellitus
NAFLD: nonalcoholic fatty liver disease
In this study, a strong association between diabetes and retinopathy was observed as previous reports[
Until now, few studies have addressed the relationship between NAFLD and retinopathy in the presence of diabetes, and there are conflicting results. Kim et al.[
Different patterns of retinopathy may be induced by different diseases, such as generalized or focal retinal arteriolar narrowing and arteriovenous nicking related to high blood pressure[
As for the participants without diabetes, there are other potential explanations for the non-significant relationship between NAFLD and retinopathy. The characteristics of NALFD and metabolic syndrome are similar[
This study has some limitations. First, only one eye was photographed in the NHANES III population, which may have caused an underestimation of the prevalence of retinopathy. Second, this study was cross-sectional; thus, we were unable to ascertain the order of onset for each event and the importance of this order. Whether there is a permanent or transient relationship between NAFLD and retinopathy is unknown. Third, ultrasonography was used to examine the national prevalence of NAFLD instead of a biopsy. Although the sensitivity and specificity differences between ultrasonography and liver biopsy are small[
Although NAFLD is viewed as a type of metabolic syndrome, no additional effects on retinopathy were observed in the group with diabetes, and, therefore it should not be considered a precipitating factor of retinopathy in the US general population. Further prospective and longitudinal studies and investigations with different demographic populations will aid in understanding the role of NAFLD in populations with or without diabetic.
No financial support of our study.