Incident Fatty Liver Research Articles

Obesity and metabolic abnormalities as risks of alcoholic fatty liver in men: NAGALA study

BackgroundHepatic steatosis has a pivotal role in the development of chronic liver diseases, even in alcohol-related liver disease. Alcoholic fatty liver disease is an important phenotype among alcohol-related liver diseases. While metabolic syndrome is a dominant risk factor of incident nonalcoholic fatty liver disease, the role of metabolic syndrome in alcoholic fatty liver disease has not been clarified yet.MethodsA retrospective cohort study was performed at a health check-up center in Japan. Subjects consisted of male participants without fatty liver who consumed ethanol of 420 g/week or higher. Adjusted hazard ratios and 95% confidence intervals at the baseline examinations for incident alcoholic fatty liver disease were estimated using Cox model.ResultsA total of 640 participants were included in this study. During 3.91 years (IQR 1.63–7.09) of follow-up, 168 new cases of alcoholic fatty liver disease developed (49.1 cases per 1000 persons per year). After adjustment for age, smoking status, alcohol consumption, the hazard ratio for a 1 kg/m2 increase in body mass index was 1.2 (1.12–1.28). The hazard ratio of subjects with high triglyceride and low high-density lipoprotein-cholesterol levels were 1.56 (1.12–2.18) and 1.52 (1.03–2.25), respectively.ConclusionsObesity, high triglyceridemia, and low high-density lipoprotein-cholesterolemia are independent risk factors of alcoholic fatty liver disease in Japanese men who consumed alcohol habitually. In people with these risks, triglyceride lowering and high-density lipoprotein-cholesterol raising by improving insulin resistance and weight maintenance in addition to abstinence from alcohol would be effective in preventing the development of alcoholic fatty liver disease.

Associations of Serum Fatty Acid Proportions with Obesity, Insulin Resistance, Blood Pressure, and Fatty Liver: The Cardiovascular Risk in Young Finns Study

The links between fatty acids (FAs) and cardiometabolic outcomes are topics of debate. Our aim was to investigate the associations between serum standardized FA percentages and cardiometabolic outcomes. We used cross-sectional (n=2187-2200 subjects, age 24-39 y, women 54%) and 10-year prospective data (n=975-1414 subjects) from the Young Finns Study. Outcomes included prevalent and incident obesity, insulin resistance (HOMA-IR index in the upper quintile), elevated blood pressure (BP; taking medication, or diastolic or systolic BP in the upper quintile), and incident nonalcoholic fatty liver. Logistic regression models were used to calculate ORs per SD increase in fatty acids (FAs). The models were adjusted for age and sex, and additionally for other potential confounders. Several cross-sectional findings were also statistically significant in prospective models (Bonferroni corrected P<0.003). In fully-adjusted models for obesity, these consisted of SFAs (OR: 1.28) and MUFAs (OR: 1.38), including palmitoleic (OR: 1.39) and oleic acids (OR: 1.37). Furthermore, PUFAs (OR: 0.70), including linoleic (OR: 0.67) and docosahexaenoic acids (OR: 0.75), were inversely related with obesity, whereas γ-linolenic acid (OR: 1.32) was positively associated with obesity. In age- and sex-adjusted models for insulin resistance, MUFAs (OR: 1.26) and oleic acid (OR: 1.25) were positively, and PUFAs (OR: 0.81), particularly linoleic acid (OR: 0.78), were inversely associated with HOMA-IR. Similarly with elevated BP, palmitic acid (OR: 1.22), MUFAs (OR: 1.28), and oleic acid (OR: 1.28) were positively associated with elevated BP, whereas PUFAs (OR: 0.77), n-6 (omega-6) PUFAs (OR: 0.79), and linoleic acid (OR: 0.77) were inversely associated. In fully-adjusted models for incident fatty liver, the most consistent predictors were high palmitic (OR: 1.61) and low linoleic acid (OR: 0.63) percentages. The n-6/n-3 (omega-3) PUFA ratio was not linked with any adverse outcomes. High serum percentages of total SFAs and MUFAs and low PUFAs, but also several specific FAs, predict future unfavorable cardiometabolic outcomes in Finnish adults.

Modeling the natural history of fatty liver using lifestyle-related risk factors: Effects of body mass index (BMI) on the life-course of fatty liver.

BackgroundIncident fatty liver increases the risk of non–alcoholic fatty liver disease (NAFLD), which may lead to end-stage liver diseases, and increase the risk of cardiovascular disease and diabetes. For its prevention, modeling the natural history of fatty liver is useful to demonstrate which lifestyle-related risk factors (e.g. body mass index and cholesterol) play the greatest role in the life-course of fatty liver.MethodsModel predictors and their predictive algorithms were determined by prospective regression analyses using 5–year data from approximately 2000 Japanese men aged 20–69 years. The participants underwent health examinations and completed questionnaires on their lifestyle behaviors annually from 2012 to 2016. The life–course of fatty liver was simulated based on this participant data using Monte Carlo simulation methods. Sensitivity analyses were performed. The validity of the model was discussed.ResultsThe body mass index (BMI) and low–density/high–density lipoprotein cholesterol (LDL–C/HDL–C) ratio significantly aided in predicting incident fatty liver. When the natural history of fatty liver was simulated using the data of participants aged 30–39 years, the prevalence increased from 20% to 32% at 40–59 years before decreasing to 24% at 70–79 years. When annual updates of BMI and LDL–C/HDL–C ratio decreased/increased by 1%, the peak prevalence of fatty liver (32%) changed by −8.0/10.7% and −1.6/1.4%, respectively.ConclusionsWe modeled the natural history of fatty liver for adult Japanese men. The model includes BMI and LDL‒C/HDL‒C ratio, which played a significant role in predicting the presence of fatty liver. Specifically, annual changes in BMI of individuals more strongly affected the life‒course of fatty liver than those in the LDL–C/HDL–C ratio. Sustainable BMI control for individuals may be the most effective option for preventing fatty liver in a population.

Reappraisal of attenuated insulin sensitivity in the evolution of non-alcoholic fatty liver disease.

It has been unknown if attenuated insulin sensitivity (Si) in non-alcoholic fatty liver disease (NAFLD) is a cause or a result. We examined the impact of attenuated Si on NAFLD evolution. We observed 4856 NAFLD- and diabetes-free participants for a mean 2.9 years. Si was indexed by single point insulin sensitivity estimator (SPISE = [600 × HDL-c0.185]/[TG0.2 × BMI1.338]), correlating with 1/HOMA-IR in an independent cohort (n = 1537, Spearman rho = 0.519, P < 0.01). Fatty liver (FL) was diagnosed by ultrasonography and diabetes by fasting plasma glucose (FPG) ≥ 7 mmol/L and/or glycohemoglobin A1c ≥ 6.5%. Multinominal comparison was performed with incident FL (FLw/oDM, n = 486), diabetes (DMw/oFL, n = 171), and FL plus diabetes (FL/diabetes, n = 58) as targets; none of the above (n = 4,138) was the control. SPISE was taken as a predictor with adjustment for covariates. Trajectory of SPISE during the 5 years before development of each condition was also assessed. With SPISE tertile 3 (>10.06) as the reference, tertile 1 (<8.07) was related to incident FLw/oDM and FL/diabetes with OR (95% CI) 3.47 (2.60-4.63) and 1.78 (1.10-2.87), respectively, and tertile 2 (8.07-10.06) related to FLw/oDM with OR (95% CI) 1.38 (1.03-1.85). Low SPISE was not significantly related to incident diabetes. At -5 years, SPISE was 12% (P < 0.05) and 13% (P < 0.01) lower in those developed FLw/oDM and FL/diabetes, respectively, than the control. At year 0, SPISE in the two groups was 18% and 21% lower than the control, respectively (P < 0.01). Attenuation of Si indexed by SPISE was a risk factor for NAFLD.

Improved Diet Quality Associates With Reduction in Liver Fat, Particularly in Individuals With High Genetic Risk Scores for Nonalcoholic Fatty Liver Disease

Dietary modification has been recommended for treatment of nonalcoholic fatty liver disease (NAFLD), although it is not clear whether improving diet quality can prevent its development. We performed a prospective study to examine the association between diet quality change and change in liver fat. We also examined the association between genetic risk score and liver fat change in individuals with different levels of diet quality change. Our study included 1521 participants who attended the seventh and eighth examinations (1998-2001 and 2005-2008) of the second-generation cohort or attended the first and second examinations (2002-2005 and 2008-2011) of the third-generation cohort in the Framingham Heart Study. The self-administered semiquantitative 126-item Harvard food frequency questionnaire was used to determine dietary intake in the year leading up to an examination. We assessed levels of liver fat using liver-phantom ratio (LPR) on computed tomography images from 2002 through 2005 and again from 2008 through 2011. LPR values are inversely related to liver fat: increased LPR indicates decreased liver fat. We examined associations of changes in 2 diet scores, the Mediterranean-style diet score (MDS) and Alternative Healthy Eating Index (AHEI), with changes in liver fat and new-onset fatty liver. We evaluated interactions between diet score change and a weighted genetic risk score for NAFLD, determined based on multiple single-nucleotide polymorphisms identified in genome-wide association studies of NAFLD. The primary outcome was change in LPR between baseline and follow-up measurement. For each 1 standard deviation increase in MDS, the LPR increased (meaning liver fat decreased) by 0.57 (95% confidence interval [CI] 0.27-0.86; P<.001) and the odds for incident fatty liver decreased by 26% (95% CI 10%-39%; P= .002). For each 1 standard deviation increase in AHEI, LPR increased by 0.56 (95% CI 0.29-0.84; P<.001) and the odds for incident fatty liver decreased by 21% (95% CI 5%-35%; P= .02). Increased diet scores were also associated with reduced odds of developing more-advanced fatty liver. Higher genetic risk scores were associated with increased liver fat accumulation in participants who had decreased MDS (P < .001) or AHEI scores (P= .001), but not in those with stable or improved diet scores (P for gene-diet interaction <.001). In an analysis of participants in the Framingham Heart Study, increasing diet quality, determined based on MDS and AHEI scores, is associated with less liver fat accumulation and reduced risk for new-onset fatty liver. An improved diet is particularly important for individuals with a high genetic risk for NAFLD.

Association of a variant in the gene encoding for ERV1/ChemR23 with reduced inflammation in visceral adipose tissue from morbidly obese individuals

Obesity comorbidities are closely associated with chronic low-grade adipose tissue inflammation. A number of SNPs associated with inflammation has been identified, underscoring the impact of genetic determinants on this process. Here, we screened SNPs in genes with pro-inflammatory (IL-1β, IL-6, STAT3 and JAK2), anti-inflammatory (IL-10 and SOCS3) and pro-resolving (ERV1/ChemR23) properties in 101 obese and 99 non-obese individuals. Among the SNPs analyzed, we identified that individuals carrying a C allele in the rs1878022 polymorphism of the ERV1/ChemR23 gene, which encodes for the receptor of the pro-resolving mediator RvE1, had increased ERV1/ChemR23 protein expression and reduced levels of the inflammatory cytokine IL-6 in adipose tissue. Moreover, patients carrying the C allele in homozygosity had lower plasma levels of IL-6, IFN-α2, IL-15, IL-1ra, IL-10, GM-CSF, G-CSF and VEGF and enhanced leukocyte responsiveness to RvE1. C-carriers also exhibited decreased TAG to HDL ratio, a surrogate marker of insulin resistance and a predictor of incident fatty liver. Finally, we confirmed in vivo that the ERV1/ChemR23 receptor regulates systemic and tissue inflammation since mice lacking ERV1/ChemR23 expression showed increased IL-6 levels in adipose tissue and peritoneal macrophages. Together, our study identified an ERV1/ChemR23 variant that protects patients with obesity from excessive inflammatory burden.

Prospective cohort study on the predictive value of serum uric acid levels to the incident nonalcoholic fatty liver disease

Objective To assess the predictive value of serum uric acid levels to the incident nonalcoholic fatty liver disease(NAFLD)in a cohort of healthy population. Methods A prospective cohort study of NAFLD incidence was conducted in Xinjiang province, from 2012 to 2014. A cohort study was performed on 2 207 subjects with no evidence of fatty liver disease by liver ultrasound and with no major risk factors for liver disease at baseline. All participants were interviewed to carry out the epidemiological questionnaire survey, physical examination, abdominal ultrasonography, as well as blood biochemistry measurements. The hazard ratios of NAFLD were compared among groups with different uric acid levels. All subjects were classified according to serum uric acid (within normal range grouped by quartile: Q1-Q4 group; above the normal range: Q5 group). Results NAFLD was newly diagnosed in 13.72% subjects within the 3-year period. The incidence of NAFLD was increased with elevated serum uric acid quartiles(P<0.01). In multivariate logistic regression, after adjustment for gender, age, race, metabolic syndrome and its components, OR for incident fatty liver in Q2 to Q5 of serum uric acid concentration as compared to Q1 were 2.509, 3.172, 3.392, and 4.041 respectively. Conclusion Elevated serum uric acid concentrations may predict NAFLD in the subjects for a regular health checkup. (Chin J Endocrinol Metab, 2017, 33: 203-207) Key words: Serum uric acid; Fatty liver; Early diagnosis; Health examination population

Bi-directional analysis between fatty liver and cardiovascular disease risk factors

The relations of non-alcoholic fatty liver disease to cardiovascular disease (CVD) risk factors are not fully understood. The objective of our study is to explore the bi-directional relationships of fatty liver to CVD risk factors. We prospectively evaluated whether liver fat predicted the development of CVD risk factors and whether CVD risk factors predicted new onset fatty liver during 6years of follow-up in middle- to older-aged Framingham Heart Study participants. We estimated liver fat using multi-detector computed tomography. We included 1051 participants (mean age 45±6years, 46% women). The prevalence of fatty liver was 18% at baseline. In participants without fatty liver at baseline, 101 participants developed incident fatty liver over approximately 6years. Baseline liver fat (per standard deviation increase) was associated with increased odds of incident hypertension (OR 1.42; 95% CI 1.15-1.76; p=0.001) and incident type 2 diabetes (OR 1.43; 95% CI 1.09-1.88, p<0.001). In a parallel analysis, individuals with hypertension (OR 3.34; 95% CI 2.04-5.49), hypertriglyceridemia (OR 3.04; 95% CI: 1.84-5.02), impaired fasting glucose (OR 2.92; 95% CI 1.76-4.82), or type 2 diabetes (OR 4.15; 95% CI 1.19-14.46) at baseline had higher odds of incident fatty liver compared to individuals without those conditions (all p<0.03). In both analyses, the observed associations remained similar after additional adjustments for measures of adiposity. The present study demonstrated bi-directional relationships between fatty liver and CVD risk factors among middle- to older-aged Framingham Heart Study participants. It is not fully understood whether non-alcoholic fatty liver (NAFLD) disease precedes or develops after increased cardiovascular disease (CVD) risk factors. The findings of our study suggest a bi-directional relationship between NAFLD and CVD risk factors.

BMI history and risk of incident fatty liver: a population-based large-scale cohort study.

Most physicians might consider that fatty liver would develop along with increasing body weight; however, an association between BMI history and incident fatty liver has not been clarified as yet. We carried out a population-based cohort study that included 4427 healthy Japanese individuals who received yearly health-checkup programs over a decade. Fatty liver was diagnosed using ultrasonography. During the observational period, 38.7% (case/N=1002/2588) of men and 17.3% (319/1847) of women were diagnosed with fatty liver. Among these, only 18.9% (189 of 1002 participants) of men and 18.5% (59 of 319) of women developed fatty liver when they reached the lifetime maximum BMI. Adjusted odds ratio of the difference between lifetime maximum BMI and BMI at age 20 years (ΔBMImax-20 years) for incident fatty liver was 1.33 [95% confidence interval (CI) 1.28-1.39, P<0.001] in men or 1.40 (95% CI 1.33-1.49, P<0.001) in women. According to receiver operator characteristic (ROC) analysis, the optimal cut-off points of ΔBMImax-20 years for incident fatty liver were 4.82 kg/m [area under ROC curve 0.70 (95% CI 0.68-0.72), P<0.001] in men and 4.11 kg/m [area under ROC curve 0.76 (95% CI 0.73-0.79), P<0.001] in women. The ΔBMImax-20 years was associated with an increased risk of incident fatty liver. In addition, more patients developed fatty liver not at the maximum point of BMI history, but after that. Therefore, it is useful to check ΔBMImax-20 years and to continue observing the individuals for detection of fatty liver.

Effect of exercise on the development of new fatty liver and the resolution of existing fatty liver

Guidelines about recommendations for amounts of exercise/physical activity are variable in non-alcoholic fatty liver disease. Our aim was to determine the amount of exercise that was associated with two outcomes: a) development of incident liver fat and b) resolution of baseline liver fat, at five-year follow-up. In an occupational health screening program, weekly frequency of exercise was assessed using the validated Korean version of the International Physical Activity Questionnaire Short Form (IPAQ-SF). Liver fat was identified by ultrasonography (3.5MHz probe) at baseline and at five-year follow-up. Fully adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs and 95% confidence intervals [CI]) for incident fatty liver and resolution of fatty liver at follow-up. 233,676 men and women were studied between 2002 and 2014. 126,811 individuals were identified without fatty liver, and of these subjects, 29,014 subjects developed incident fatty liver during follow-up. At baseline, there were 42,536 individuals with liver fat and of these individuals, fatty liver resolved in 14,514, during follow-up. After full adjustment, compared to no exercise, exercise was associated with benefit for both outcomes; for exercise ⩾5times per week for incident fatty liver: HR 0.86 (95% CI 0.80,0.92), p<0.001, and for resolution of fatty liver HR 1.40 (95% CI 1.25,1.55), p<0.001. Moderate to vigorous exercise is beneficial in decreasing risk of development of new fatty liver or improving resolution of existing fatty liver during 5years of follow-up. The amount of exercise/physical activity to benefit fatty liver disease in non-alcoholic fatty liver disease is not known. In a large study of free-living people, our aim was to determine the amount of exercise that was linked with a decrease in new fatty liver and also improvement of existing fatty liver over 5years of follow-up. Compared to no exercise, exercise ⩾5times per week (lasting at least 10min on each occasion) was linked to a highly significantly benefit for both a decrease in new fatty liver and also improvement of existing fatty liver.

Alcohol and Steatosis: The Japanese Paradox

1. Background In this issue of EBioMedicine, Roerecke and Colleagues report that, in Japan, alcohol consumption as low as b20 g daily was associated with significant protection from incident and prevalent fatty liver; however, no such association was found in countries other than Japan (Roerecke et al., 2016). This systematic review is based on the analysis of 18 articles (11 of which are from Japan) which recruited, overall, 99,370 participants, 25,662 of whom had steatosis. Moreover, sex was an important modifier of the risk of fatty liver when the whole range of alcohol consumption was considered. Indeed, while in men a non-linear and inverse dose-response risk relationship was reported, in women the risk curve was J-shaped and turned to a detrimental association with increasing alcohol consumption. Finally, binge drinking was consistently associated with higher risk of liver steatosis.

Change in fatty liver status and 5-year risk of incident metabolic syndrome: a retrospective cohort study.

IntroductionFatty liver is associated with metabolic syndrome (MetS) but it may also occur without MetS. Whether resolution of fatty liver in the general population affects risk of MetS is unknown. Our aim was to determine whether a change in fatty liver status (either the development of new fatty liver or the resolution of existing fatty liver) would modify the risk of de novo MetS.MethodsTwo thousand eighty-nine people without hypertension, diabetes, and MetS were examined at baseline and at 5-year follow-up using a retrospective cohort study design. Fatty liver status was assessed at baseline and at follow-up by ultrasonography. Adjusted hazard ratios (aHR) and 95 % confidence intervals (CIs) for de novo MetS at follow-up were calculated controlling for the potential confounders, compared to the reference group (people who never had fatty liver at baseline and follow-up).ResultsDuring follow-up, fatty liver developed in 251 people and fatty liver resolved in 112 people. After the adjustment for multiple confounders, persisting fatty liver and incident fatty liver development were associated with de novo MetS, with aHR of 2.60 (95 % CIs [1.61,4.20]) and 3.31 (95 % CIs [1.99,5.51]), respectively. Risk of new MetS in resolved fatty liver group was attenuated with insignificant aHR of 1.29 accompanying 95 % CIs of 0.60 and 2.80.DiscussionDevelopment or maintenance of fatty liver is positively associated with occurrence of new MetS. Resolution of fatty liver status has similar risk of de novo MetS with those who never had fatty liver. Therefore, cautious management is needed with those with fatty liver.

Triglycerides to high-density lipoprotein cholesterol ratio is an independent predictor of incident fatty liver; a population-based cohort study.

Triglycerides (TG) to high-density lipoprotein cholesterol (HDL-C) ratio (TG/HDL-C) has been recommended for surrogates of insulin resistance. However, it remains to be elucidated the association between TG/HDL-C and incident fatty liver. To investigate the association between TG/HDL-C and incident fatty liver. We performed population-based historical cohort study consisted with 4518 healthy Japanese who received yearly health-checkup programmes over decade. Fatty liver was diagnosed using ultrasonography. During the observation periods, 38.8% (case/N = 1023/2637) of men and 17.2% (case/N = 324/1881) of women developed fatty liver. Adjusting odds ratio of TG/HDL-C for incident fatty liver were 1.59 (95% confidence interval (CI) 1.42-1.79, P < 0.0001) in men and 2.50 (95% CI 1.80-3.51, P < 0.0001) in women. In addition, adjusting odds ratio of TG/HDL-C for incident non-alcoholic fatty liver disease were 1.55 (95% CI 1.35-1.77, P < 0.0001) in men and 2.72 (95% CI 1.88-3.95, P < 0.0001) in women. According to the receiver operator characteristic (ROC) analysis, the optimal cut-off point of TG/HDL-C for incident fatty liver was 0.88 (area under the ROC curve (AUC) 0.67 [95% CI 0.65-0.69], sensitivity = 0.64, specificity = 0.60, P < 0.0001) in men and 0.64 (AUC 0.69 [95% CI 0.66-0.72], sensitivity = 0.50, specificity = 0.78, P < 0.0001) in women. The TG/HDL-C could predict the incident fatty liver. Thus, it is important to check TG/HDL-C and lifestyles modification is needed for preventing future fatty liver disease in patients with high TG/HDL-C.

Incidence of non-alcoholic fatty liver disease in Hong Kong: A population study with paired proton-magnetic resonance spectroscopy

Because abdominal ultrasonography cannot reliably quantify hepatic steatosis, accurate data on the incidence of non-alcoholic fatty liver disease (NAFLD) are lacking. We aimed to study the population incidence of NAFLD with state-of-the-art non-invasive tests. This was a prospective cohort study. The intrahepatic triglyceride (IHTG) content was measured serially with proton-magnetic resonance spectroscopy in community subjects. Transient elastography was performed to assess liver fibrosis. 565 subjects (mean age 48 years, 62.7% women) without NAFLD at baseline underwent follow-up assessment after a median interval of 47 months (range 34-60 months). 78 (13.8%) subjects developed incident fatty liver with a mean IHTG content of 8.9% (SD 5.3%). 16 (20.5%) subjects had an IHTG content ⩾ 11.0% suggestive of moderate to severe steatosis. After excluding 2 men with significant alcohol consumption, the population incidence of NAFLD at 3-5 years was 13.5% (95% CI 10.6-16.3%; 3.4% per year). Only 1 subject with incident NAFLD had high liver stiffness (11.1 kPa) suggestive of advanced fibrosis. Metabolic syndrome at baseline was the strongest predictor of incident fatty liver. Incident central obesity developed in 31.0% of subjects with incident fatty liver and 5.6% of those without (p<0.001). No subject with incident fatty liver had regression of impaired fasting glucose, which occurred in 51.1% of those without incident fatty liver (p=0.001). 13.5% of the Hong Kong Chinese adult population develop NAFLD in 3-5 years, but few have severe steatosis or advanced fibrosis. Metabolic syndrome is the most important risk factor of incident NAFLD.

Physical activity and risk of fatty liver in people with different levels of alcohol consumption: a prospective cohort study

ObjectiveTo investigate whether physical activity affects the future incidence of fatty liver in people with never-moderate and heavy alcohol consumption.DesignProspective cohort study.SettingHealth check-up programme at Meiji Yasuda Shinjuku Medical Center...

Development of new fatty liver, or resolution of existing fatty liver, over five years of follow-up, and risk of incident hypertension

Approximately 50% of hypertensive patients have non-alcoholic fatty liver disease (NAFLD), but whether change in fatty liver status over time modifies risk of developing hypertension is uncertain. Our aim was to determine whether a change in fatty liver status (either development of new fatty liver, or resolution of existing fatty liver) over five years modified risk of incident hypertension at five year follow-up. 11,448 patients without hypertension were examined at baseline and at five year follow-up, using a retrospective cohort study design. Fatty liver status (absent or present) was assessed at baseline and follow-up using standard ultrasound criteria. Adjusted odds ratios (aOR) and 95% confidence intervals (CIs) for incident hypertension at follow-up were estimated controlling for potential confounders, compared to the reference group (patients who did not have fatty liver at either baseline or follow-up). 911 patients developed incident hypertension. Incident fatty liver developed during follow-up in 1418 patients and fatty liver at baseline resolved during follow-up in 684 patients. Developing incident fatty liver was associated with incident hypertension, even after adjustment for multiple confounders (aOR=1.60 (95% CI 1.30, 1.96; p<0.001). Further adjustment for change in body mass index between baseline and follow-up only slightly attenuated this association (aOR=1.36 (95% CI 1.10, 1.67; p=0.004). With resolution of fatty liver at follow-up, risk of incident hypertension was not different from the reference group (aOR=1.21 (95% CI 0.90, 1.63; p=0.21). Development of incident fatty liver is associated with increased risk of hypertension.

Prognostic implications for insulin-sensitive and insulin-resistant normal-weight and obese individuals from a population-based cohort

There are few prospective data on the prognosis of insulin-sensitive and insulin-resistant normal-weight (NW) or obese individuals. The estimated liver fat content, incidences of hyperglycemia and cardiovascular disease, and all-cause and cardiovascular mortality rates were investigated in a population-based cohort of 1658 individuals who were categorized according to BMI and insulin resistance as defined by HOMA-IR values ≥2.5 and the presence of metabolic syndrome. This was a prospective cohort study with a 9-y follow-up. Anthropometric values, blood pressure, and blood metabolic variables were measured, and information on vital status was collected from demographic files at follow-up. A total of 137 of 677 NW individuals (20%) were classified as insulin resistant and normal weight (IR-NW), and 72 of 330 obese individuals (22%) were classified as insulin sensitive and obese (IS-obese). Incidences of diabetes, impaired fasting glucose, and cardiovascular events were 0.4%, 6.3%, and 3.3%, respectively, in insulin-sensitive and normal-weight (IS-NW) individuals (reference category); 5.8%, 10.2%, and 6.6%, respectively, in IR-NW individuals; and 5.6%, 8.3%, and 8.3%, respectively, in IS-obese individuals. In a multiple logistic regression model, risks of incident hyperglycemia and cardiovascular events increased in both groups compared with in the reference category [HR (95% CI): 2.54 (1.42, 4.55) and 1.98 (0.86, 4.54) in IR-NW subjects; 2.16 (1.01, 4.63) and 2.76 (1.05, 7.28) in IS-obese subjects]. The estimated liver fat content significantly increased during follow-up only in the IR-NW group in the same model. Cardiovascular mortality was 2-3-fold higher in IR-NW and IS-obese than in IS-NW individuals in a Cox regression model. Our data refute the existence of healthy obese phenotypes because IS-obese individuals showed increased cardiometabolic risk. The existence of unhealthy NW phenotypes is supported by their increased risk of incident hyperglycemia, fatty liver, cardiovascular events, and death.

Predicting incident fatty liver using simple cardio-metabolic risk factors at baseline

BackgroundNon alcoholic fatty liver disease (NAFLD) is associated with increased risk of type 2 diabetes and chronic liver disease but identifying patients who have NAFLD without resorting to expensive imaging tests is challenging. In order to help identify people for imaging investigation of the liver who are at high risk of NAFLD, our aim was to: a) identify easily measured risk factors at baseline that were independently associated with incident fatty liver at follow up, and then b) to test the diagnostic performance of thresholds of these factors at baseline, to predict or to exclude incident fatty liver at follow up.Methods2589 people with absence of fatty liver on ultrasound examination at baseline were re-examined after a mean of 4.4 years in a Korean occupational cohort study. Multi-variable logistic regression analyses were used to identify baseline factors that were independently associated with incident fatty liver at follow up. The diagnostic performance of thresholds of these baseline factors to identify people with incident fatty liver at follow-up was assessed using receiver operating characteristic (ROC) curves.Results430 incident cases of fatty liver were identified. Several factors were independently associated with incident fatty liver: increased triglyceride (per mmol/l increase) OR 1.378 [95%CIs 1.179, 1.611], p < 0.0001; glucose (per mmol/l increase) OR 1.215 [95%CIs 1.042, 1.416], p = 0.013; waist (per cm increase) OR 1.078 [95%CIs 1.057, 1.099], p < 0.001; ALT (per IU/L increase) OR 1.009 [95%CIs 1.002, 1.017], p = 0.016; and platelets (per 1x109/L increase) OR 1.004 [1.001, 1.006], p = 0.001; were each independently associated with incident fatty liver. Binary thresholds of the five factors were applied and the area under the ROC curve for incident fatty liver was 0.75 (95%CI 0.72–0.78) for the combination of all five factors above these thresholds.ConclusionSimple risk factors that overlap considerably with risk factors for type 2 diabetes allow identification of people at high risk of incident fatty liver at who use of hepatic imaging could be targeted.

Serum ferritin levels predict incident non-alcoholic fatty liver disease in healthy Korean men

Little research has been done to examine the temporal relationship between serum ferritin and the development of nonalcoholic fatty liver disease. The aim of this study was to examine whether serum ferritin levels predict incident fatty liver in non-diabetic men. The study cohort comprised 2410 healthy Korean male who were aged 30 to 59years old with no evidence of ultrasonographically detectable fatty liver (USFL) at baseline. Alcohol intake was assessed with a self-reported questionnaire. At each visit, biochemical and anthropometric measurements and abdominal ultrasonography were done. Cox proportional hazard models were used to calculate the adjusted hazard ratios in separate models for USFL. During 7545.9 person-years of follow-up, 586 participants developed USFL. The hazard ratio (95% confidence interval) for incident USFL comparing the highest quartile of serum ferritin level to the lowest quartile was 1.54 (1.21–1.94) after adjusting for age, body mass index, smoking, alcohol intake, and exercise. That association remained significant after further adjustment for cardiovascular risk factors and in time-dependent models. The association between serum ferritin and incident USFL was still significant in the non-overweight group or the no current smoker group. Serum ferritin level was an independent risk factor of incident fatty liver detected by ultrasonography even in non-obese, healthy Korean men. Increased serum ferritin levels appear to be an early predictor for incident fatty liver.

Serum uric acid levels predict incident nonalcoholic fatty liver disease in healthy Korean men

The objective of the study was to assess the prospective association between serum uric acid levels and incident nonalcoholic fatty liver disease in a cohort of healthy Korean men. A cohort study was performed on 5741 Korean men, 30 to 59 years of age, with no evidence of fatty liver disease on liver ultrasound and with no major risk factors for liver disease at baseline. Study participants were followed in annual or biennial health examinations between 2002 and 2008. The presence of fatty liver was determined at each examination by ultrasound. Cox proportional hazards models were used to evaluate the association of baseline and time-dependent levels of serum uric acid with incident fatty liver, adjusted for potential confounders. During 23 995 person-years of follow-up, 1717 participants developed fatty liver on ultrasound examination. After adjustment for age, body mass index, smoking, and alcohol intake, the hazard ratios (95% confidence intervals) for incident fatty liver comparing quartiles 2 to 4 of serum uric acid to quartile 1 were 1.17 (1.01-1.37), 1.28 (1.11-1.48), and 1.51 (1.31-1.73), respectively ( P for trend = .001). The adjusted hazard ratio comparing participants with hyperuricemia (serum uric acid ≥7.0 mg/dL) to those with normouricemia (<7.0 mg/dL) was 1.29 (1.14-1.46). A graded and statistically significant association persisted after adjusting for other cardiometabolic factors and also in time-dependent models. Serum uric acid was an independent risk factor of incident fatty liver detected by ultrasonography. Additional research should clarify the mechanisms underlying this association and the role of hyperuricemia in the development of fatty liver.