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1.  Traditional but Not HIV-Related Factors Are Associated with Nonalcoholic Fatty Liver Disease in Asian Patients with HIV-1 Infection 
PLoS ONE  2014;9(1):e87596.
The prevalence and factors associated with nonalcoholic fatty liver disease (NAFLD) are largely unknown in HIV-1 monoinfected patients.
The present study elucidated the prevalence and factors associated with NAFLD among Asian patients with HIV-1 infection who underwent abdominal ultrasonography between January 2004 and March 2013. Diagnosis of NAFLD was based on the liver to kidney contrast and diffusion in hepatic echogenicity. Uni- and multi-variate logistic regression analyses were applied to estimate factors associated with NAFLD.
435 Asian patients free of chronic hepatitis B or C virus infection and without excessive alcohol intake were analyzed. NAFLD was diagnosed in 135 (31%) patients. Obesity (BMI >30 kg/m2) was evident in 18 (4.1%) patients, and BMI was >25 kg/m2 in 103 (24%). Multivariate analysis identified higher BMI (per 1 kg/m2 increment, adjusted OR = 1.198; 95% CI, 1.112–1.290; p<0.001), dyslipidemia (adjusted OR = 2.045; 95% CI, 1.183–3.538; p = 0.010), and higher ALT to AST ratio (per 1 increment, adjusted OR = 3.557; 95% CI, 2.129–5.941; p<0.001) as significant factors associated with NAFLD. No HIV-specific variables, including treatment with dideoxynucleoside analogues (didanosine, stavudine, and zalcitabine) and cumulative duration of antiretroviral therapy (ART), were associated with NAFLD.
The incidence of NALFD among Asian patients with HIV-1 infection is similar to that in Western countries. NAFLD was associated with high BMI, dyslipidemia, and high ALT/AST ratio, but not with HIV-related factors. The results highlight the importance of early recognition and management of NAFLD and traditional factors associated with NAFLD for Asian patients with HIV-1 infection.
PMCID: PMC3909216  PMID: 24498148
2.  Nonalcoholic fatty liver disease is associated with low HDL cholesterol and coronary angioplasty in patients with type 2 diabetes 
There is evidence that nonalcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular risk. In this study we examined factors associated with the presence of NAFLD and the prevalence of macroangiopathy in patients with type 2 diabetes.
Subjects were 101 consecutive patients with type 2 diabetes: 72 with NAFLD and 29 free of NAFLD. NAFLD was diagnosed by ultrasonography. Serum lipids were measured enzymatically and glycated hemoglobin HbA1c was measured by HPLC.
The mean age of patients was 53.1±10.4 in the NAFLD group and 44.9±10.9 years in patients without NAFLD (p<0.001). The mean duration of diabetes was 10±6.3 years in patients with NAFLD and 15.1±7.8 years in those without NAFLD (p<0.001). Mean values of glycated hemoglobin A1c were similar in both groups. Patients with NAFLD were characterized by a significantly higher prevalence of coronary angioplasty (20.8% vs. 0%, p=0.008). Overweight and obesity were observed in a higher percentage of patients with NAFLD (p<0.001). Patients with NAFLD were characterized by significantly higher values of alanine transaminase (p=0.033), and lower serum concentrations of HDL-cholesterol (p<0.001) and creatinine (p=0.034). Logistic regression analysis (p<0.001) revealed that NAFLD was positively associated with waist circumference above normal (women >80 cm, men >94 cm) (p=0.0083) and alanine transaminase activity (p=0.0164), and negatively with creatinine concentration (p=0.0226). In a second logistic regression model (p<0.001), waist circumference (p<0.007) and total cholesterol (p<0.008) were positive predictors, while HDL-C (p<0.003) was a negative predictor of NAFLD.
The results of the study suggest that NAFLD is associated with visceral obesity and low HDL-cholesterol in patients with type 2 diabetes.
PMCID: PMC3871489  PMID: 24336007
fatty liver disease; diabetes type 2; diabetic macroangiopathy; obesity
3.  Development and validation of a simple index system to predict nonalcoholic fatty liver disease 
Abdominal ultrasonography is useful for the detection and diagnosis of nonalcoholic fatty liver disease (NAFLD). The aims of this study were to establish a predictive model for the selection of subjects for abdominal ultrasonography for the diagnosis of NAFLD and to assess validity of the model.
The subjects included 901 people who visited the health examination center of the Busan Medical Center. We conducted multiple logistic regression analyses of potential risk factors to identify independent risk factors for NAFLD, and developed an index system.
Four independent risk factors were identified. The index system was developed by assigning 1 clinical scoring point to approximately 0.7 logistic regression coefficients to each factor as follows: alanine aminotransferase/aspartate aminotransferase ratio >1.5 (odds ratio [OR], 2.22; 95% confidence interval [CI], 1.21-4.07; P=0.010), 1 point; γ-glutamyl transpeptidase >50 (OR, 2.15; 95% CI, 1.13-4.07; P=0.019), 1 point; triglyceride >150 mg/dL (OR, 1.92; 95% CI, 1.14-3.24; P=0.015), 1 point; 23 kg/m2≤BMI<25 kg/m2 (OR, 3.68; 95% CI, 2.05-6.63; P<0.001), 2 points; and BMI 25 kg/m2 (OR, 7.65; 95% CI, 4.29-13.62; P<0.001), 3 points. The area under the receiver operating characteristics curve was 0.797 (95% CI, 0.751-0.842), and when 3 points was used as a cut-off value, the sensitivity and specificity were 71.7% and 75.9%, respectively.
NAFLD can be predicted through the clinical application of the index system established herein. If abdominal ultrasonography is used for high-risk patients, NAFLD will be diagnosed and managed in its early stage.
PMCID: PMC3304618  PMID: 21494074
Nonalcoholic fatty liver disease; Diagnosis; Ultrasonography
4.  Association between Noninvasive Fibrosis Markers and Chronic Kidney Disease among Adults with Nonalcoholic Fatty Liver Disease 
PLoS ONE  2014;9(2):e88569.
Evidence suggests that nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are associated with an increased risk of chronic kidney disease (CKD). In this study we aimed to evaluate whether the severity of liver fibrosis estimated by NAFLD fibrosis score is associated with higher prevalence of CKD in individuals with NAFLD. To this end NAFLD fibrosis score and estimated glomerular filtration rate (eGFR) were assessed in 570 White individuals with ultrasonography-diagnosed NAFLD. As compared with subjects at low probability of liver fibrosis, individuals at high and intermediate probability showed an unfavorable cardio-metabolic risk profile having significantly higher values of waist circumference, insulin resistance, high sensitivity C-reactive protein, fibrinogen, uric acid and lower insulin-like growth factor-1 levels. Individuals at high and intermediate probability of liver fibrosis have lower eGFR after adjustment for gender, smoking, glucose tolerance status, homeostasis model assessment index of insulin resistance (HOMA-IR index), diagnosis of metabolic syndrome, statin therapy, anti-diabetes and anti-hypertensive treatments (P = 0.001). Individuals at high probability of liver fibrosis had a 5.1-fold increased risk of having CKD (OR 5.13, 95%CI 1.13–23.28; P = 0.03) as compared with individuals at low probability after adjustment for age, gender, and BMI. After adjustment for glucose tolerance status, statin therapy, and anti-hypertensive treatment in addition to gender, individuals at high probability of liver fibrosis had a 3.9-fold increased risk of CKD (OR 3.94, 95%CI 1.11–14.05; P = 0.03) as compared with individuals at low probability. In conclusion, advanced liver fibrosis, determined by noninvasive fibrosis markers, is associated with CKD independently from other known factors.
PMCID: PMC3919760  PMID: 24520400
5.  Association between Insulin Resistance, Metabolic Syndrome and Nonalcoholic Fatty Liver Disease in Chinese Adults 
The aim of this study was to assess the association between insulin resistance, metabolic syndrome and nonalcoholic fatty liver disease (NAFLD) in Chinese adults.
Fifty five subjects with NAFLD and 55 controls were enrolled for the study. Waist circumference, blood pressure, plasma triglyceride, high density lipoprotein cholesterol and fasting plasma glucose concentrations and homeostasis model assessment of insulin resistance (HOMA-IR) values as an index used to quantify insulin resistance were measured and analyzed. Logistic regression was analyzed to predict independent risk factors of NAFLD.
The prevalence of metabolic syndrome in NAFLD group was obviously higher than in controls group (47.3% VS 3.6%, P<0.001). There were all significant differences of each component of metabolic syndrome and HOMA-IR values in comparison of nonalcoholic fatty liver disease (NAFLD) and controls group. In a logistic regression analysis, age, diastolic blood pressure, waist circumference and HOMA-IR were the covariates independently associated with the presence of NAFLD (Odds Ratio=1.107, 1.083, 1.218 and 16.836; 95% CI: 1.011∼1.211, 1.001∼1.173, 1.083∼1.370 and 3.626∼78.168, respectively; P<0.05)
NAFLD was closely associated with metabolic syndrome and insulin resistance was a very strong predictor of NAFLD.
PMCID: PMC3481655  PMID: 23113121
Insulin Resistance; Metabolic syndrome; Nonalcoholic Fatty Liver Disease; China
6.  Impact of Visceral Fat on the Metabolic Syndrome and Nonalcoholic Fatty Liver Disease 
Journal of Korean Medical Science  2008;23(5):789-795.
Visceral fat has been reported to be associated with nonalcoholic fatty liver disease (NAFLD) and the metabolic syndrome (MetS). We assessed the prevalence of both NAFLD and the MetS, measured visceral fat thickness (VFT), and estimated the physical activity indexes of 224 relatively healthy hospital workers. We also investigated the associations between both VFT and physical activity index and each of NAFLD and the MetS. The MetS was diagnosed according to the guidelines outlined by the Adult Treatment Panel III, and NAFLD was diagnosed by ultrasonography. Subjects with hepatitis B and C infections and those reporting moderate alcohol consumption were excluded from the study. The prevalence of the MetS was 11.6% and that of NAFLD was 41.5%. Many subjects with the MetS had NAFLD (73.1%), and some subjects with NAFLD (20.4%) also had several components of the MetS (p=0.001). VFT was significantly increased by both the addition of components of the MetS and the severity of NAFLD (p<0.001). In addition, VFT was independently associated with NAFLD (odds ratio [OR], 1.10; 95% confidence interval [CI], 1.02-1.19) in subjects with more than 2 components of the MetS. In contrast, habitual physical activity was reversely associated with NAFLD (OR, 0.29; 95% CI, 0.10-0.87). In conclusion, an increased visceral fat content and reduced physical activity could be not only biological markers but also therapeutic targets in the treatment of NAFLD and the MetS.
PMCID: PMC2580019  PMID: 18955783
Nonalcoholic Fatty Liver Disease; Metabolic Syndrome; Intra-Abdominal Fat; Work Index
7.  Prevalence of hepatic steatosis in women with polycystic ovary syndrome 
Nonalcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) both are known to be associated with insulin resistance and metabolic syndrome (MS). The aim of the study was to determine the presence of NAFLD and associated factors of hepatic steatosis in women with PCOS.
A cross-sectional hospital based study of 54 women with PCOS and 55 healthy controls who were age and weight matched were included. Anthropometric parameters, biochemical and hormonal investigations were done in all the patients. Insulin resistance was calculated by Homeostasis model assessment (HOMA). Abdominal ultrasonography and biochemical tests were used to determine the presence of hepatic steatosis after excluding other causes liver disease.
Women with PCOS had a higher prevalence of hepatic steatosis (67% vs 25%, P = 0.001) MS (35% vs. 7%, P < 0.01) and elevated transaminases (31% vs. 7%, P = 0.03) than controls. All patients with PCOS and controls with MS had presence of hepatic steatosis. Age, BMI, waist-hip ratio, HOMA-IR, HDL and PCOS diagnosis were the factors associated with presence of hepatic steatosis.
NAFLD is commonly present in women with PCOS in combination with other metabolic derangements. Evaluation for liver disease should be considered at an earlier age in women with PCOS, particularly those who have an evidence of MS.
PMCID: PMC3713587  PMID: 23869143
Insulin resistance; metabolic syndrome; non-alcoholic fatty liver disease; polycystic ovary syndrome
8.  Nonalcoholic Fatty Liver Disease (NAFLD) among HIV-Infected Persons 
To describe the prevalence and factors associated with nonalcoholic fatty liver disease (NAFLD) among HIV-infected persons not infected with hepatitis C virus (HCV).
A cross-sectional study among HIV-infected patients in a large HIV clinic.
NAFLD was defined as steatosis among patients without viral hepatitis (B or C) co-infection or excessive alcohol use. The prevalence of NAFLD was identified by ultrasound examination evaluated by two radiologists blinded to the clinic information; liver biopsies were performed on a subset of the study population. Factors associated with NAFLD evaluated by proportional odds logistic regression models.
Sixty-seven (31%) of 216 patients had NAFLD based on ultrasound evaluation. Among those with NAFLD, steatosis was graded as mild in 60%, moderate in 28%, and severe/ marked in 12%. Factors associated with the degree of steatosis on ultrasound examination in the multivariate model included increased waist circumference (odds ratio [OR] 2.1 per 10 cm, p<0.001), elevated triglycerides (OR= 1.2 per 100 mg/dl, p=0.03), and lower HDL levels (OR 0.7, p=0.03). African Americans were less likely to have NAFLD compared to Caucasians (14% vs. 35%), although this did not reach statistical significance (OR= 0.4, p=0.08). Similar associations were noted for the subset of patients diagnosed by liver biopsy. CD4 cell count, HIV viral load, duration of HIV infection, and antiretroviral medications were not independent risk factors associated with NAFLD after adjustment for dyslipidemia or waist circumference.
NAFLD was common among this cohort of HIV-infected, HCV-seronegative patients. NAFLD was associated with a greater waist circumference, low HDL and high triglyceride levels. Antiretroviral medications were not associated with NAFLD; prospective studies are needed to confirm this finding.
PMCID: PMC2782375  PMID: 19225402
HIV; NAFLD; steatosis; liver disease; antiretroviral medication
9.  The Severity of Fatty Liver Disease Relating to Metabolic Abnormalities Independently Predicts Coronary Calcification 
Background. Nonalcoholic fatty liver disease (NAFLD) is one of the metabolic disorders presented in liver. The relationship between severity of NAFLD and coronary atherosclerotic burden remains largely unknown. Methods and Materials. We analyzed subjects undergoing coronary calcium score evaluation by computed tomography (MDCT) and fatty liver assessment using abdominal ultrasonography. Framingham risk score (FRS) and metabolic risk score (MRS) were obtained in all subjects. A graded, semiquantitative score was established to quantify the severity of NAFLD. Multivariate logistic regression analysis was used to depict the association between NAFLD and calcium score. Results. Of all, 342 participants (female: 22.5%, mean age: 48.7 ± 7.0 years) met the sufficient information rendering detailed analysis. The severity of NAFLD was positively associated with MRS (X2 = 6.12, trend P < 0.001) and FRS (X2 = 5.88, trend P < 0.001). After multivariable adjustment for clinical variables and life styles, the existence of moderate to severe NAFLD was independently associated with abnormal calcium score (P < 0.05). Conclusion. The severity of NAFLD correlated well with metabolic abnormality and was independently predict coronary calcification beyond clinical factors. Our data suggests that NAFLD based on ultrasonogram could positively reflect the burden of coronary calcification.
PMCID: PMC3255298  PMID: 22254139
10.  Active Smoking, Passive Smoking, and Risk of Nonalcoholic Fatty Liver Disease (NAFLD): A Population-Based Study in China 
Journal of Epidemiology  2013;23(2):115-121.
The effect of active smoking on development of nonalcoholic fatty liver disease (NAFLD) is controversial, and there are limited clinical data on the relationship between passive smoking and NAFLD. We investigated whether active and passive smoking are associated with NAFLD.
A total of 8580 subjects (2691 men) aged 40 years or older participated in a community-based survey in Shanghai, China. Information on active and passive smoking was collected using a validated questionnaire. NAFLD was diagnosed by abdominal B-mode ultrasound testing and serum liver enzymes.
NAFLD prevalence was 29.4% in never smokers, 34.2% in former smokers, 27.8% in light smokers (<20 cigarettes/day), 30.8% in moderate smokers (20–39 cigarettes/day), and 43.5% in heavy smokers (≥40 cigarettes/day). Fully adjusted logistic regression analyses revealed that, as compared with never smoking, former and heavy smoking were associated with increased risk of prevalent NAFLD, with odds ratios of 1.45 (95% CI 1.05–2.00) and 2.29 (95% CI 1.30–4.03), respectively. Active smoking and body mass index (BMI) had a synergistic effect on the risk of prevalent NAFLD; the combination of these risk factors was associated with the highest observed odds ratio for NAFLD: 8.58. In never-smoking women, passive smoking during both childhood and adulthood was associated with a 25% increase in the risk of prevalent NAFLD (OR = 1.25, 95% CI 1.05–1.50) as compared with no passive smoking.
Passive smoking and heavy active smoking are associated with prevalent NAFLD in middle-aged and elderly Chinese. Active smoking and BMI have a synergistic effect on prevalent NAFLD.
PMCID: PMC3700247  PMID: 23399520
active tobacco smoking; passive tobacco smoking; fatty liver
11.  Nonalcoholic Fatty Liver Disease and Cardiovascular Disease: Has the Time Come for Cardiologists to Be Hepatologists? 
Journal of Obesity  2012;2012:483135.
Nonalcoholic fatty liver disease (NAFLD) is prevalent in people with the metabolic syndrome and type 2 diabetes and is present in up to one-third of the general population. Evidence is now accumulating that NAFLD is associated with obesity and diabetes and may serve as a predictor of cardiovascular disease (CVD). The possible mechanisms linking NAFLD and CVD include inflammation and oxidative stress, hyperlipidaemia, insulin resistance, and direct impact of NAFLD on coronary arteries and left ventricular dysfunction. In addition, several studies suggest that NAFLD is associated with high risk of CVD and atherosclerosis such as carotid artery wall thickness and lower endothelial flow-mediated vasodilation independently of classical risk factors and components of the metabolic syndrome. It is not yet clear how treatment of NAFLD will modulate the risk of CVD. Furthermore, studies are urgently needed to establish (i) the pathophysiology of CVD with NAFLD and (ii) the benefit of early diagnosis and treatment of CVD in patients with NAFLD. In the absence of biochemical markers, it is crucial that screening and surveillance strategies are adopted in clinical practice in the growing number of patients with NAFLD and at risk of developing CVD. Importantly, the current evidence suggest that statins are safe and effective treatment for CVD in individuals with NAFLD.
PMCID: PMC3540795  PMID: 23320150
12.  Aging is a risk factor of nonalcoholic fatty liver disease in premenopausal women 
AIM: To clarify the relationship between age, menopause, and nonalcoholic fatty liver disease (NAFLD) in women.
METHODS: We conducted a follow-up study on nonalcoholic fatty liver disease by using abdominal ultrasonography, and investigated the relationship of age and menopause with the development of NAFLD in women. We followed 1829 women and 2572 men (response rate, 86%) selected in 2001 to represent the non-institutionalized adult population of Gifu, Japan. Data collected included self-reported medical history, lifestyle factors, and menopausal status. The postmenopausal state was defined as beginning 1 year after the cessation of menses. We diagnosed NAFLD with the aid of abdominal ultrasonography by using diagnostic criteria described previously.
RESULTS: The prevalence of NAFLD in women increases with age, but does not alter with age in men. Furthermore, the prevalence of NAFLD in premenopausal women (6%) was lower than that in men (24%) and in postmenopausal women (15%). The associations of the postmenopausal state and hormone replacement therapy with NAFLD were statistically significant in a univariate logistic regression model. At the follow-up examination, 67 women (5%) were newly diagnosed with NAFLD. The incidence of NAFLD was 3.5% (28/802) in premenopausal women, 7.5% (4/53) in menopausal women, 6.1% (24/392) in postmenopausal women, and 5.3% (11/206) in women receiving hormone replacement therapy. The weight gain in premenopausal women was equal to that in postmenopausal women. Metabolic syndrome and weight gain were independent risk factors for NAFLD in pre- and postmenopausal women, but age was an independent risk factor in premenopausal women only.
CONCLUSION: Aging is a risk factor for NAFLD in premenopausal women, independent of weight gain or influence of metabolic syndrome.
PMCID: PMC3261540  PMID: 22294826
Nonalcoholic fatty liver disease; Cardiovascular disease; Risk factor; Steatohepatitis; Postmenopausal women
13.  Enigmatic Ectopic Fat: Prevalence of Nonalcoholic Fatty Pancreas Disease and Its Associated Factors in a Chinese Population 
Fatty infiltration of the pancreas is an enigmatic manifestation of ectopic fat deposition in obesity. Studies have shown that pancreatic lipid accumulation interferes with insulin secretion in humans. However, the prevalence of fatty pancreas and its associated factors in the general population remain unclear. The aim of this study was to investigate the prevalence of fatty pancreas and its association with diabetes, nonalcoholic fatty liver disease (NAFLD), and cardiometabolic risk factors in a Chinese population.
Methods and Results
This was a cross‐sectional study. A total of 8097 subjects with or without fatty pancreas (n=1297 and 6800, respectively) were recruited. Each subject was assessed by using abdominal sonography to diagnose NAFLD and fatty pancreas. Clinical and metabolic parameters were compared between groups, and their associations with fatty pancreas were examined. The prevalence of fatty pancreas was 16%. The fatty pancreas group had a significantly greater proportion of subjects with diabetes (12.6% versus 5.2%) and NAFLD (67.2% versus 35.1%) than did the non–fatty pancreas group (P<0.001). In the logistic regression analysis, age (P<0.001), general or central obesity (P<0.001), diabetes (P<0.001), and NAFLD (P<0.001) were independently associated with fatty pancreas after adjustment for sex, lipid profile, alanine transaminase/aspartate transaminase ratio, hypertension, smoking, alcohol drinking, and exercise.
The prevalence of fatty pancreas is high in the general population. Both diabetes and NAFLD are important associated factors of fatty pancreas, independent of age, sex, adiposity, and other cardiometabolic risk factors.
PMCID: PMC3959709  PMID: 24572250
diabetes; nonalcoholic fatty liver disease; nonalcoholic fatty pancreas disease; obesity
14.  The influence of waist circumference on insulin resistance and nonalcoholic fatty liver disease in apparently healthy Korean adults 
Clinical and molecular hepatology  2013;19(2):140-147.
Waist circumference (WC) is a risk factor for metabolic syndrome and is related to insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD). The purpose of this study was to determine the association between WC and IR and NAFLD in apparently healthy Korean adults.
The volunteers included in this cross-sectional study comprised 9,159 adults (5,052 men, 4,107 women) who participated in a comprehensive health checkup program. IR was evaluated by the homeostasis model assessment of IR (HOMA-IR) and was considered to be present when the HOMA-IR score was >2. NAFLD was evaluated by ultrasound examination. Elevated alanine aminotransferase (ALT) was defined as >40 IU/L in men and >35 IU/L in women. Logistic regression was performed to determine the odds ratios (ORs) and 95% confidence intervals (95% CIs) for NAFLD, IR, and ALT according to categorized levels of WC.
NAFLD was found in 2,553 (27.9%) of the participants (82.6% men, 17.4% women), while IR and elevated ALT were found in 17.2% (68.1% men, 31.9% women) and 10% (83% men, 17% women), respectively. After adjusting for confounding factors, the prevalence of NAFLD, IR, and elevated ALT was significantly associated with increases in WC quartile: highest quartile for NAFLD in men, OR=15.539, 95% CI=12.687-19.033; highest quartile for NAFLD in women, OR=48.732, 95% CI=23.918-99.288 (P<0.001); and highest quartile for IR in men, OR=17.576, 95% CI=13.283-23.255; highest quartile for IR in women, OR=11.078, 95% CI=7.813-15.708 (P<0.001); highest quartile for elevated ALT in men, OR=7.952, 95% CI=6.046-10.459; and highest quartile for elevated ALT in women, OR=8.487, 95% CI=4.679-15.395 (P<0.001).
WC contributes to IR and NAFLD in apparently healthy Korean adults, and thus may be an important factor in the development of IR and NAFLD.
PMCID: PMC3701846  PMID: 23837138
Waist circumference; Insulin resistance; Nonalcoholic fatty liver disease
15.  A Cohort Study of Serum Bilirubin Levels and Incident Non-Alcoholic Fatty Liver Disease in Middle Aged Korean Workers 
PLoS ONE  2012;7(5):e37241.
Serum bilirubin may have potent antioxidant and cytoprotective effects. Serum bilirubin levels are inversely associated with several cardiovascular and metabolic endpoints, but their association with nonalcoholic fatty liver disease (NAFLD) has not been investigated except for a single cross-sectional study in a pediatric population. We assessed the prospective association between serum bilirubin concentrations (total, direct, and indirect) and the risk for NAFLD.
Methods and Findings
We performed a cohort study in 5,900 Korean men, 30 to 59 years of age, with no evidence of liver disease and no major risk factors for liver disease at baseline. Study participants were followed in annual or biennial health examinations between 2002 and 2009. The presence of fatty liver was determined at each visit by ultrasonography. We observed 1,938 incident cases of NAFLD during 28,101.8 person-years of follow-up. Increasing levels of serum direct bilirubin were progressively associated with a decreasing incidence of NAFLD. In age-adjusted models, the hazard ratio for NAFLD comparing the highest to the lowest quartile of serum direct bilirubin levels was 0.61 (95% CI 0.54–0.68). The association persisted after adjusting for multiple metabolic parameters (hazard ratio comparing the highest to the lowest quartile 0.86, 95% CI 0.76–0.98; P trend = 0.039). Neither serum total nor indirect bilirubin levels were significantly associated with the incidence of NAFLD.
In this large prospective study, higher serum direct bilirubin levels were significantly associated with a lower risk of developing NAFLD, even adjusting for a variety of metabolic parameters. Further research is needed to elucidate the mechanisms underlying this association and to establish the role of serum direct bilirubin as a marker for NAFLD risk.
PMCID: PMC3352875  PMID: 22615952
16.  Evaluation of atherosclerotic findings in patients with nonalcoholic fatty liver disease 
Nonalcoholic fatty liver disease (NAFLD), a highly prevalent condition, is a feature of metabolic syndrome and is characterized by excessive accumulation of fat in the liver cells. The purpose of this study was to investigate the association between NAFLD and carotid intima-media thickness (CIMT) as an independent risk factor for atherosclerosis.
We examined 250 consecutive patients with ultrasonographically confirmed NAFLD and 85 age-matched and gender-matched controls with normal parenchymal liver echogenicity for determination of CIMT and presence of carotid atherosclerotic plaque.
Compared with control subjects, patients with NAFLD showed an increased mean CIMT (0.81 ± 0.14 mm) compared with control subjects (0.58 ± 0.15 mm). This difference was statistically significant (P = 0.001). After performing multivariate analysis, the presence of NAFLD was associated with abnormal CIMT independent of other atherogenic risk factors or its association with metabolic syndrome.
NAFLD can be an independent risk factor for developing atherosclerosis. Therefore, NAFLD with and without metabolic syndrome can be associated with increased CIMT and increased risk of cardiovascular events in patients with NAFLD incidentally diagnosed on abdominal ultrasonography.
PMCID: PMC3219757  PMID: 22114515
nonalcoholic fatty liver disease; metabolic syndrome; atherosclerosis; carotid intima media thickness; risk factor
17.  Decreased Circulating Endothelial Progenitor Cell Levels and Function in Patients with Nonalcoholic Fatty Liver Disease 
PLoS ONE  2012;7(2):e31799.
Nonalcoholic fatty liver disease (NAFLD) is associated with advanced atherosclerosis and a higher risk of cardiovascular disease. Increasing evidence suggests that injured endothelial monolayer is regenerated by circulating bone marrow derived-endothelial progenitor cells (EPCs), and levels of circulating EPCs reflect vascular repair capacity. However, the relation between NAFLD and EPC remains unclear. Here, we tested the hypothesis that patients with nonalcoholic fatty liver disease (NAFLD) might have decreased endothelial progenitor cell (EPC) levels and attenuated EPC function.
Methods and Results
A total of 312 consecutive patients undergoing elective coronary angiography because of suspected coronary artery disease were screened and received examinations of abdominal ultrasonography between July 2009 and November 2010. Finally, 34 patients with an ultrasonographic diagnosis of NAFLD, and 68 age- and sex-matched controls without NAFLD were enrolled. Flow cytometry with quantification of EPC markers (defined as CD34+, CD34+KDR+, and CD34+KDR+CD133+) in peripheral blood samples was used to assess circulating EPC numbers. The adhesive function, and migration, and tube formation capacities of EPCs were also determined in NAFLD patients and controls. Patients with NAFLD had a significantly higher incidence of metabolic syndrome, previous myocardial infarction, hyperuricemia, and higher waist circumference, body mass index, fasting glucose and triglyceride levels. In addition, patients with NAFLD had significantly decreased circulating EPC levels (all P<0.05), attenuated EPC functions, and enhanced systemic inflammation compared to controls. Multivariate logistic regression analysis showed that circulating EPC level (CD34+KDR+ [cells/105 events]) was an independent reverse predictor of NAFLD (Odds ratio: 0.78; 95% confidence interval: 0.69–0.89, P<0.001).
NAFLD patients have decreased circulating EPC numbers and functions than those without NAFLD, which may be one of the mechanisms to explain atherosclerotic disease progression and enhanced cardiovascular risk in patients with NAFLD.
PMCID: PMC3280999  PMID: 22359630
18.  Role of Body Mass Index, Waist-to-Height and Waist-to-Hip Ratio in Prediction of Nonalcoholic Fatty Liver Disease 
Objective. To investigate the anthropometric indicators that can effectively predict the nonalcoholic fatty liver disease (NAFLD). Methods. The height, body weight, waist and hip circumference were measured, and body mass index (BMI), waist-to-height (WHtR) and waist-to-hip ratio (WHR) were calculated. M-H chi square test, logistic regression analysis, and receiver-operating characteristic (ROC) curve were employed for the analysis of risk factors. Patients or Materials. 490 patients were recruited, of whom 250 were diagnosed as NAFLD and 240 as non-NAFLD (control group). Results. Compared with the control group, the BMI, WHR, and WHtR were significantly higher in patients with NAFLD. Logistic regression analysis showed that BMI and WHR were effective prognostic factors of NAFLD. In addition, WHR plays a more important role in prediction of NAFLD by the area under curve. Conclusion. WHR is closely related to the occurrence of NAFLD. We assume that WHR is beneficial for the diagnosis NAFLD.
PMCID: PMC3369513  PMID: 22701476
19.  Nonalcoholic fatty liver disease and mitochondrial dysfunction 
Nonalcoholic fatty liver disease (NAFLD) includes hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. NAFLD is the most common liver disorder in the United States and worldwide. Due to the rapid rise of the metabolic syndrome, the prevalence of NAFLD has recently dramatically increased and will continue to increase. NAFLD has also the potential to progress to hepatocellular carcinoma (HCC) or liver failure. NAFLD is strongly linked to caloric overconsumption, physical inactivity, insulin resistance and genetic factors. Although significant progress in understanding the pathogenesis of NAFLD has been achieved in years, the primary metabolic abnormalities leading to lipid accumulation within hepatocytes has remained poorly understood. Mitochondria are critical metabolic organelles serving as “cellular power plants”. Accumulating evidence indicate that hepatic mitochondrial dysfunction is crucial to the pathogenesis of NAFLD. This review is focused on the significant role of mitochondria in the development of NAFLD.
PMCID: PMC2675113  PMID: 18186554
Nonalcoholic fatty liver disease; Mitochondria; Fatty acid oxidation; Liver
20.  Cardiovascular Risk Factors and the Metabolic Syndrome in Pediatric Nonalcoholic Fatty Liver Disease 
Circulation  2008;118(3):277-283.
Nonalcoholic fatty liver disease (NAFLD), the most common cause of liver disease in children, is associated with obesity and insulin resistance. However, the relationship between NAFLD and cardiovascular risk factors in children is not fully understood. The objective of this study was to determine the association between NAFLD and the presence of metabolic syndrome in overweight and obese children.
Methods and Results
This case-control study of 150 overweight children with biopsy-proven NAFLD and 150 overweight children without NAFLD compared rates of metabolic syndrome using Adult Treatment Panel III criteria. Cases and controls were well matched in age, sex, and severity of obesity. Children with NAFLD had significantly higher fasting glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, triglycerides, systolic blood pressure, and diastolic blood pressure than overweight and obese children without NAFLD. Subjects with NAFLD also had significantly lower high-density lipoprotein cholesterol than controls. After adjustment for age, sex, race, ethnicity, body mass index, and hyperinsulinemia, children with metabolic syndrome had 5.0 (95% confidence interval, 2.6 to 9.7) times the odds of having NAFLD as overweight and obese children without metabolic syndrome.
NAFLD in overweight and obese children is strongly associated with multiple cardiovascular risk factors. The identification of NAFLD in a child should prompt global counseling to address nutrition, physical activity, and avoidance of smoking to prevent the development of cardiovascular disease and type 2 diabetes.
PMCID: PMC2996820  PMID: 18591439
blood pressure; lipids; liver; obesity; pediatrics
21.  Pediatric nonalcoholic fatty liver disease, metabolic syndrome and cardiovascular risk 
Nonalcoholic fatty liver disease (NAFLD) encompasses a range of liver histology severity and outcomes in the absence of chronic alcohol use. The mildest form is simple steatosis in which triglycerides accumulate within hepatocytes. A more advanced form of NAFLD, non-alcoholic steatohepatitis, includes inflammation and liver cell injury, progressive to cryptogenic cirrhosis. NAFLD has become the most common cause of chronic liver disease in children and adolescents. The recent rise in the prevalence rates of overweight and obesity likely explains the NAFLD epidemic worldwide. NAFLD is strongly associated with abdominal obesity, type 2 diabetes, and dyslipidemia, and most patients have evidence of insulin resistance. Thus, NAFLD shares many features of the metabolic syndrome (MetS), a highly atherogenic condition, and this has stimulated interest in the possible role of NAFLD in the development of atherosclerosis. Accumulating evidence suggests that NAFLD is associated with a significantly greater overall mortality than in the general population, as well as with increased prevalence of cardiovascular disease (CVD), independently of classical atherosclerotic risk factors. Yet, several studies including the pediatric population have reported independent associations between NAFLD and impaired flow-mediated vasodilatation and increased carotid artery intimal medial thickness-two reliable markers of subclinical atherosclerosis-after adjusting for cardiovascular risk factors and MetS. Therefore, the rising prevalence of obesity-related MetS and NAFLD in childhood may lead to a parallel increase in adverse cardiovascular outcomes. In children, the cardiovascular system remains plastic and damage-reversible if early and appropriate interventions are established effectively. Therapeutic goals for NAFLD should address nutrition, physical activity, and avoidance of smoking to prevent not only end-stage liver disease but also CVD.
PMCID: PMC3158407  PMID: 21912450
Nonalcoholic fatty liver disease; Metabolic syndrome; Cardiovascular risk; Children
22.  A Simple Indian Diabetes Risk Score Could Help Identify Nondiabetic Individuals at High Risk of Non-Alcoholic Fatty Liver Disease (CURES-117) 
We aim to determine whether a simple Indian diabetes risk score (IDRS) is associated with individuals with non-alcoholic fatty liver disease (NAFLD) among nondiabetic Asian Indians.
Nondiabetic participants (n = 409) were selected from the Chennai Urban Rural Epidemiology Study. Mean age was 40 ± 11.9 years, mean body mass index was 23.2 ± 3.9 kg/m2, and 224 (54.8%) were women. The IDRS was classified as high (≥60), medium (30–50), and low (<30) risk. Non-alcoholic fatty liver disease was assessed by high-resolution β mode ultrasonography. To determine the factors associated with NAFLD, a univariate analysis was first done and a stepwise logistic regression analysis was done based on the factors associated with NAFLD. Biochemical and anthropometric measurements were obtained using standardized procedures.
The overall prevalence of NAFLD was 24.7% (101/409 participants), and it was significantly higher among those with a high (30.4%) and medium IDRS (21%) compared with the low IDRS group (15.8%; trend chi square; p = .022). In stepwise logistic regression, IDRS was associated with NAFLD with an adjusted odds ratio of 1.78 (95% confidence interval 1.04–3.06), even after adjusting for potential confounders.
The IDRS can be used as the initial step to screen individuals at high risk of NAFLD in the community.
PMCID: PMC3570885  PMID: 23294790
Asian Indians; diabetes; Indian diabetes risk score; non-alcoholic fatty liver disease; screening; South Asians
23.  Non-alcoholic fatty liver disease and liver transplantation: Outcomes and advances 
Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent causes of chronic liver disease worldwide. In the last decade it has become the third most common indication for liver transplantation in the United States. Increasing prevalence of NAFLD in the general population also poses a risk to organ donation, as allograft steatosis can be associated with non-function of the graft. Post-transplant survival is comparable between NAFLD and non-NAFLD causes of liver disease, although long term outcomes beyond 10 year are lacking. NAFLD can recur in the allograft frequently although thus far post transplant survival has not been impacted. De novo NAFLD can also occur in the allograft of patients transplanted for non-NAFLD liver disease. Predictors for NAFLD post-transplant recurrence include obesity, hyperlipidemia and diabetes as well as steroid dose after liver transplantation. A polymorphism in PNPLA3 that mediates triglyceride hydrolysis and is linked to pre-transplant risk of obesity and NAFLD has also been linked to post transplant NAFLD risk. Although immunosuppression side effects potentiate obesity and the metabolic syndrome, studies of immunosuppression modulation and trials of specific immunosuppression regimens post-transplant are lacking in this patient population. Based on pre-transplant data, sustained weight loss through diet and exercise is the most effective therapy for NAFLD. Other agents occasionally utilized in NAFLD prior to transplantation include vitamin E and insulin-sensitizing agents. Studies of these therapies are lacking in the post-transplant population. A multimodality and multidisciplinary approach to treatment should be utilized in management of post-transplant NAFLD.
PMCID: PMC3882389  PMID: 24409043
Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Liver transplantation; Metabolic syndrome; Outcomes; Management
24.  Non-Alcoholic Fatty Liver Disease and Cardiovascular Risk 
Nonalcoholic fatty liver disease (NAFLD) is a very common cause of chronic liver disease in United States. A large proportion of patients with NAFLD have co-existing metabolic syndrome which is a major risk factor for cardiovascular disease. A strong association between NAFLD and cardiovascular disease has been long suspected and recent studies have confirmed that cardiovascular disease is the single most important cause of mortality in these patient population. There is a suggestion that NAFLD may pose cardiovascular risk above and beyond that is conferred by traditional cardiovascular risk factors (e.g., dyslipidemia, diabetes and smoking). Health care providers managing patients with NAFLD should recognize this increased cardiovascular risk and should undertake early aggressive risk factor modification.
PMCID: PMC2732016  PMID: 19166659
25.  The efficacy of aspartate aminotransferase-to-platelet ratio index for assessing hepatic fibrosis in childhood nonalcoholic steatohepatitis for medical practice 
Korean Journal of Pediatrics  2013;56(1):19-25.
Childhood obesity is associated with nonalcoholic fatty liver disease (NAFLD), and it has become one of the most common causes of childhood chronic liver diseases which significant as a cause of liver related mortality and morbidity in children in the United States. The development of simpler and easier clinical indices for medical practice is needed to identify advanced hepatic fibrosis in childhood NAFLD instead of invasive method like liver biopsy. FibroScan and aspartate aminotransferase (AST)-to-platelet ratio index (APRI) have been proposed as a simple and noninvasive predictor to evaluate hepatic fibrosis in several liver diseases. APRI could be a good alternative to detect pathologic change in childhood NAFLD. The purpose of this study is to validate the efficacy of APRI for assessing hepatic fibrosis in childhood NAFLD based on FibroScan.
This study included 23 children with NAFLD who underwent FibroScan. Clinical, laboratory and radiological evaluation including APRI was performed. To confirm the result of this study, 6 patients received liver biopsy.
Factors associated with hepatic fibrosis (stiffness measurement >5.9 kPa Fibroscan) were triglyceride, AST, alanine aminotransferase, platelet count, APRI and collagen IV. In multivariate analysis, APRI were correlated with hepatic fibrosis (>5.9 kPa). In receiver operating characteristics curve, APRI of meaningful fibrosis (cutoff value, 0.4669; area under the receiver operating characteristics, 0.875) presented sensitivity of 94%, specificity of 66%, positive predictive value of 94%, and negative predictive value of 64%.
APRI might be a noninvasive, simple, and readily available method for medical practice to predict hepatic fibrosis of childhood NAFLD.
PMCID: PMC3564026  PMID: 23390441
Nonalcoholic fatty liver disease; Hepatic fibrosis; APRI; Child

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