Statin use and development and progression of non-alcohol fatty liver disease based on ultrasonography: a cohort study.

INTRODUCTION: Non-alcohol fatty liver disease (NAFLD) has emerged as a public health issue, while no drugs have been specifically approved for treatment. This study aimed to examine the association between statin use and NAFLD occurrence, progression, and regression. METHODS: A cohort study was designed based on the Kailuan Study and electronic medical records (EMRs) from the Kailuan General Hospital. Participants aged 18 years with statin indication, including statin and non-statin users, were enrolled in 2010-2017. Propensity score-matched cohorts were also used. RESULTS: In the entire cohort, 21 229 non-NAFLD and 22 419 NAFLD patients (including 12 818 mild NAFLD) were included in the final analysis. After a median follow-up of about four years, the incidence of NAFLD occurrence and progression for statin users were lower than those for non-statin users (occurrence: 84.7 vs. 106.5/1000 person-years; progression: 60.7 vs. 75.5/1000 person-years). Compared with non-statin users, the risk of NAFLD occurrence (hazard ratio [HR]: 0.78, 95% confidence interval [CI]: 0.70-0.87) and regression (HR [95%CI], 0.71[0.60-0.84]) was decreased in statin users. The significantly negative association was only observed in those with cumulative statin duration ≥ 2 years (HR [95%CI] for occurrence 0.56 [0.46-0.69] vs. 0.52 [0.30-0.90] for progression) and those with low or moderate ASCVD-risk (HR [95%CI] for occurrence 0.74 [0.66-0.82] vs. 0.68 [0.57-0.80] for progression). No significant correlation was observed between statin use, statin use duration, and NAFLD regression. The PS-matched cohort had similar results. CONCLUSION: Taking statin may decrease the risk of NAFLD occurrence and progression in the population with statin indication, suggesting the potential role of statin in both primary and secondary prevention strategies for NAFLD, especially among those with low or moderate ASCVD risk.

Association between remnant cholesterol and metabolic dysfunction-associated steatotic liver disease in the elderly.

BACKGROUND & AIMS: Whether maintaining optimal remnant cholesterol (RC) levels later in life may improve metabolic dysfunction-associated steatotic liver disease (MASLD) outcomes remained ambiguous. This study aimed to investigate the relationship between RC and MASLD in the elderly Chinese population. METHODS: A total of 131,868 subjects aged ≥ 65 years were included in this study. The association of RC with MASLD, and severity of MASLD was analyzed by logistic regression. In addition, stratified analysis was conducted to test the potential interaction. RESULTS: MASLD prevalence and RC concentration decreased with age. After adjustment for possible confounders, the odds ratio of MASLD at the highest quartile of RC compared to the lowest quartile was 1.587(95% CI: 1.524-1.652), and this effect remained in MASLD with liver fibrosis. Stratified analysis showed a more prominent effect on the MASLD in males, those aged 65-69 years, those without central obesity, those with diabetes, and normal level of total cholesterol, low-density lipoprotein cholesterol (Pfor interaction<0.05). CONCLUSIONS: In the elderly subset of the Chinese population, higher RC levels achieved a significant risk effect against MASLD. More RC monitoring should be given to older for the prevention and intervention of MASLD.

Blood manganese and non-alcoholic fatty liver disease in a high manganese exposure area in China.

BACKGROUND AND AIMS: Manganese (Mn) deficiency and intoxication may affect nonalcoholic fatty liver disease (NAFLD) risk differently. We aimed to explore the association between blood Mn and NAFLD in an area with high Mn exposure in drinking water. METHODS: We conducted a case-control study among 1407 patients with NAFLD and 1774 sex- and age-matched healthy controls in a physical examination population in Zhoushan hospital, Zhejiang province in China. We used the restricted cubic splines method to investigate the dose-response relationship. Logistic regression models were applied to determine the risk of NAFLD, and severity of NAFLD. RESULTS: The blood Mn concentration was higher in the NAFLD group than in the control group in women (16.1 ± 6.2 µg/L vs. 14.7 ± 6.4 µg/L, P = 0.022) and men (14.5 ± 6.3 µg/L vs. 13.6 ± 6.8 µg/L, P < 0.001). We found an inverted L shape relationship between blood Mn and NAFLD in both women and men. Compared to the lowest quartile, the adjusted odds ratio (OR) and 95% confidence interval (CI) of NAFLD for the highest quartile group was 1.646(1.222,2.217), 1.494(1.082,2.061), and 3.146(1.285,7.701) for the total population, men, and women. The positive relationship was only observed in those with fibrosis-4 score < 1.30 and normal alanine transaminase. Stratified analysis showed an interaction between smoking (P = 0.073), alcohol drinking (P = 0.013), and Mn, with a more prominent effect on the NAFLD in the never-smokers (OR = 2.153, 95% CI 1.408-3.290) and drinkers (OR = 2.596, 95% CI 1.608-4.191). CONCLUSION: Higher blood Mn is associated with an elevated NAFLD risk in the high Mn exposure areas, especially in nonsmokers and drinkers. Further studies are needed to verify this result in the areas with high Mn exposure.

Essential metal mixtures exposure and NAFLD: A cohort-based case-control study in northern Chinese male adults.

Epidemiologic evidence on metal mixtures and non-alcoholic fatty liver disease (NAFLD) is limited. We aimed to assess the relationship between multiple metal co-exposure and NAFLD among male adults in Northern China. We conducted a cohort-based case-control study with 648 NAFLD and 648 non-NAFLD males. Seven metal concentrations (calcium, copper, iron, magnesium, manganese, selenium, and zinc) were determined in the blood. We used logistic regression and restricted cubic splines (RCS) to estimate the associations between the single metal and NAFLD. The impact of metal mixtures was quantified by the environmental risk score (ERS) in the adaptive elastic-net regression, and the association with NAFLD was estimated by logistic regression. Age-adjusted RCS showed linear relationships between blood calcium, selenium, and NAFLD. Blood copper, iron, magnesium, and manganese were non-linearly associated with NAFLD. Single metal analysis observed significant relationships between calcium, copper, manganese, and NAFLD, with the adjusted odds ratio (95% confidence interval) for quartile 1 vs. quartile 4 of 1.99 (1.30, 3.05), 2.36 (1.52, 3.64), and 1.77 (1.22, 2.55), respectively. However, metal mixtures analysis revealed one squared term (copper [ß = -0.146]) and five metal-metal interactions (calcium × copper [ß = 0.200], copper × magnesium [ß = 0.188], copper × selenium [ß = 0.188], iron × magnesium [ß = 0.143], magnesium × selenium [ß = -0.297]) except the three main effects. Higher ERS indicated a higher risk for NAFLD when exposed to metal mixtures, with an adjusted odds ratio = 6.50 (95% confidence interval: 4.36-9.69) for quartile 4 vs. quartile 1. Mediation analysis suggested that 11.66% of the effect of ERS on NAFLD was suppressed by fasting blood glucose. Our results show that exposure to metal mixtures is associated with a higher risk for NAFLD than the single metal. Interactions between metals suggest the importance of balancing the various metals for health benefits. Prospective cohorts and mechanism studies need to confirm the findings.

[Egg consumption and non-alcoholic fatty liver disease: a prospective cohort study].

OBJECTIVE: To explore the association between egg consumption and the risk of non-alcoholic fatty liver disease(NAFLD), which will provide epidemiological evidence for NAFLD prevention. METHODS: A total of 6734 non-NAFLD participants(5500 men and 1234 women, aged(45±14) years old)in the Kailuan cohort followed up in 2014-2015 were enrolled. Semi-quantitative food frequency questionnaires were used to collect the diet frequency, including the consumption of eggs, over the past years. Then the score of dietary approaches to stop hypertension(DASH) was calculated. Abdominal ultrasound was applied for fatty liver diagnosis. The Kaplan-Meier method was used to estimate the cumulative incidences of NAFLD for the three groups(0-4, 5-7 and >7 eggs/week). Furthermore, Cox regression models under various adjusted factors were used to compare the risks of NAFLD. RESULTS: During the median follow-up of 45 months, 1484 NAFLDs were identified among 6734 non-NAFLD participants. The 4-year cumulative incidence rates of NAFLD for the individuals consuming 0-4, 5-7, and >7 eggs/week were 27.1%, 19.9% and 29.6%(P<0.05). The DASH score was significantly higher in those who consumed 5-7 eggs/week than in the other two groups(P<0.001). After adjusting confounders, including DASH score and dietary cholesterol, we found that compared with those consuming 5-7 eggs/week, the individuals with 0-4 and >7 eggs/week had a higher NAFLD hazard, with hazard ratios(95% confidence interval) of 1.20(1.03, 1.41) and 1.25(1.06, 1.47), respectively. The association was more significant in the population with a higher DASH score(P_(interaction)=0.02). CONCLUSION: Eating 5-7 eggs/week may have the lowest risk of NAFLD, suggesting taking a moderate amount of eggs to prevent NAFLD, even if the overall diet quality is relatively healthy.

Association Between Blood Calcium, Magnesium, and Non-alcoholic Fatty Liver Disease in Adults: a Cohort-Based Case-Control Study.

Previous studies have shown that calcium (Ca), magnesium (Mg), and Ca/Mg ratio are associated with inflammation and metabolic disorders, but their relationship with non-alcoholic fatty liver disease (NAFLD) is unclear. Thus, we aimed to explore the association between Ca, Mg, Ca/Mg ratio, and NAFLD in Chinese adults. We conducted a case-control study based on the Kailuan Cohort in China, including 1816 cases and 1111 gender- and age-matched controls. Dose-response relationships between blood Ca, Mg, Ca/Mg ratio, and NAFLD were evaluated using restricted cubic splines. Odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated by logistic regression models. A negative association between blood Ca (overall association P < 0.001 and linear association P < 0.001) and NAFLD as well as Ca/Mg ratio (overall association P = 0.002 and linear association P = 0.024) and NAFLD was observed. Compared with the highest quartile, the adjusted OR (95% CI) for the lowest quartile of Ca and Ca/Mg ratio was 2.116 (1.679-2.667) and 1.358 (1.076-1.713), respectively. A U-shaped relationship was found for blood Mg and NAFLD, with the highest OR of 1.685 in the lowest quartile group when using the second quartile as a reference. Additionally, we observed the interaction between alanine aminotransferase and blood Ca (P = 0.024), total cholesterol (P = 0.017), low-density lipoprotein-cholesterol (P = 0.013), and blood Mg, as well as total cholesterol and Ca/Mg ratio (P = 0.014). Lower blood Ca and Ca/Mg ratio were significantly associated with the risk of NAFLD. Liver function or lipid metabolism parameters may modify their association, suggesting an individualized prevention strategy for NAFLD.

Outcomes of subjects who are lean, overweight or obese with nonalcoholic fatty liver disease: A cohort study in China.

The ability to determine the prognosis of lean nonalcoholic fatty liver disease (NAFLD) is essential for decision making in clinical settings. Using a large community-based Chinese cohort, we aimed to investigate NAFLD outcomes by body mass index (BMI). We used the restricted cubic splines method to investigate the dose-response relationship between BMI and outcomes in subjects with NAFLD and those without NAFLD. We included 73,907 subjects from the Kailuan cohort and grouped all subjects into four phenotypes by using NAFLD and BMI (<23 kg/m2 ). The probability of developing outcomes for individuals with lean NAFLD (LN), overweight/obese NAFLD (ON), overweight/obese non-NAFLD (ONN), and lean non-NAFLD (LNN) was estimated. We found a U-shaped association between BMI and death but a linear positive association concerning cardiovascular disease (CVD) after adjusting for age and other covariates. Compared with the LNN group, the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of the LN, ON, and ONN groups were 1.30 (1.14-1.49), 0.86 (0.80-0.91), 0.84 (0.80-0.89) for all-cause death, 2.61 (1.13-6.03), 0.74 (0.44-1.26), 1.10 (0.70-1.74) for liver-related death, 2.12 (1.46-3.08), 1.23 (0.99-1.54), 1.19 (0.98-1.43) for digestive system cancers, and 2.04 (1.40-2.96), 1.30 (1.05-1.61), 1.21 (1.01-1.46) for obesity-related cancers. Subjects with LN had a significantly higher risk of colorectal cancer and esophagus cancer. However, the ON group had the highest CVD risk (HR, 1.39; 95% CI, 1.27-1.52). The LN group with hypertension had a higher risk of adverse outcomes, and those without hypertension had a similar risk compared to LNN. Conclusion: Subjects with LN may experience a higher risk of all-cause death, digestive system cancers, and obesity-related cancers than the other three groups but a lower risk of CVD than ON subjects. LN with hypertension may be a high-risk phenotype.

Short-term weight loss decreased the risk of chronic kidney disease in men with incident nonalcoholic fatty liver disease.

OBJECTIVE: The study aimed to examine the association of obesity and chronic kidney disease (CKD) after nonalcoholic fatty liver disease (NAFLD) occurrence. METHODS: The study enrolled 10,311 adult men with newly diagnosed NAFLD and without CKD in the Kailuan cohort (2006-2013). The Fine-Gray model was used to compare advanced CKD risk in NAFLD with different baseline or trajectories in obesity measures. RESULTS: During a median follow-up of 10 years, maintaining normal waist circumference or waist-hip ratio, or transition from obesity to nonobesity determined by BMI, decreased 31% (hazard ratio [HR] = 0.69; 95% CI: 0.51-0.93), 34% (HR = 0.66; 95% CI: 0.45-0.95), and 38% (HR = 0.62; 95% CI: 0.40-0.96) of the CKD hazard compared with the "constantly without obesity" subgroup, respectively. NAFLD patients with at least 10% weight loss (HR = 0.58; 95% CI: 0.34-0.97) and with 7.0% to 9.9% weight loss (HR = 0.53; 95% CI: 0.28-0.99) had a lower risk for CKD than those with weight change ±4.9%. Compared with the stable weight population, the lower risk of ≥7% weight loss was observed only in patients with elevated blood pressure (adjusted HR = 0.48; 95% CI: 0.28-0.81). CONCLUSIONS: Short-term weight loss of at least 7% could decrease CKD risk, especially among patients with obesity and elevated blood pressure. It is important to monitor waist circumference, waist-hip ratio, and weight for NAFLD management.

Adherence to the dietary approaches to stop hypertension diet and non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: The evidence of the relationship between dietary approaches to stop hypertension (DASH) and non-alcoholic fatty liver disease (NAFLD) is limited. Thus, we conducted a cohort-based case-control study to examine whether adherence to the DASH diet was associated with lower NAFLD risk in China. METHODS: We included 11 888 participants (2529 incident NAFLD and 9359 non-NAFLD) from the Kailuan cohort with no history of hepatitis B/C infection and alcohol drinking. DASH score was calculated based on the energy-adjusted consumption of vegetables, fruits, dairy, beans, grains, meats, fat, sodium and beverage, collected by a validated food frequency questionnaire. We used Logistic regression analysis to determine the NAFLD's risk according to the DASH score. RESULTS: Higher DASH score was associated with lower risk of NAFLD. Compared with the lowest quintile of DASH score, the highest DASH quintile had a lower risk of occurring NAFLD, with odds ratio (OR) of 0.82 (95% confidence interval [CI]: 0.70-0.96) in the multivariate model. Stratified analysis showed that the inverse association was only observed in women (OR = 0.67, 95% CI: 0.48-0.94), and participants with overweight/obesity (OR = 0.79, 95% CI: 0.66-0.94), fasting blood glucose <6.1 mmol/L (OR = 0.80, 95%: 0.67-0.96), low density lipoprotein ≥3.4 mmol/L (OR = 0.71, 95% CI: 0.53-0.96), high density lipoprotein ≥1.0 mmol/L (OR = 0.81, 95% CI: 0.69-0.96), ALT < 40 U/L (OR = 0.79, 95% CI:0.67-0.93) and C-reactive protein ≥2.0 mg/L (OR = 0.56, 95% CI: 0.40-0.78). CONCLUSIONS: Adherence to the DASH diet was inversely associated with a lower risk of NAFLD in the Chinese population. DASH diet should be highly recommended, especially for women and people with overweight/obesity and a high CRP level.

Metabolic Dysfunction-associated Fatty Liver Disease and Mortality Among Chinese Adults: a Prospective Cohort Study.

CONTEXT: Nonalcoholic fatty liver disease (NAFLD) was renamed metabolic dysfunction associated with fatty liver disease (MAFLD) recently. OBJECTIVE: We aimed to explore the risk of all-cause deaths in MAFLD participants and compare it with NAFLD in Chinese adults. METHODS: We enrolled 152 139 participants with abdominal ultrasonography in the Kailuan Cohort from 2006 to 2012. We categorized the participants into MAFLD and non-MAFLD, NAFLD and non-NAFLD, and 4 groups of Neither FLD, MAFLD only, NAFLD only, and MAFLD-NAFLD, respectively. We used Cox regression models to estimate the hazard ratios (HRs) and 95% CI of death. RESULTS: The prevalence of MAFLD and NAFLD was 31.5% and 27.3%, respectively. After a median follow-up of 12.7 years, MAFLD and NAFLD both were associated with increased mortality, especially in men younger than 40 years, with HR (95% CI) of 1.51 (1.19-1.93) and 1.37 (1.06-1.78), respectively. The MAFLD-only group had higher mortality than the NAFLD-only in males 60 years or older (adjusted HR = 1.43; 95% CI, 1.00-2.03) and lower risk in males aged 40 to 59 years (adjusted HR = 0.65; 95% CI, 0.48-0.90). MAFLD with overweight/obesity-only decreased, but those with diabetes and/or metabolic dysregulation increased the risk of death. MAFLD with positive hepatitis B surface antigen and/or excessive alcohol consumption further increased the risk of death, especially in men younger than 40 years (HR = 9.86; 95% CI, 2.44-39.98). CONCLUSION: MAFLD was associated with increased all-cause mortality among the Chinese population, which was different according to the status of overweight/obesity, diabetes, other metabolic indicators, and second causes. MAFLD patients should be managed by metabolic indicators and second causes to fulfill precise treatment and management.

Blood manganese and nonalcoholic fatty liver disease: A cohort-based case-control study.

BACKGROUND & AIMS: As both a toxic and essential trace element in humans, limited research focuses on the association between blood manganese (Mn) and nonalcoholic fatty liver disease (NAFLD). We aimed to assess blood Mn concentration and its relationship with NAFLD among adults in Northern China. METHODS: We conducted a cohort-based case-control study among 1816 patients with NAFLD (970 males and 846 females) and 1111 healthy controls (598 males and 513 females). We used the restricted cubic splines method to investigate the potential non-linear relationship and logistic regression models to analyze the association between blood Mn and NAFLD. RESULTS: The median (p25, p75) of blood Mn concentration in males was 10.08 (8.42,11.98) µg/L, higher than that in females [9.79 (8.01,12.04)] µg/L, P = 0.011. Compared with the tertile 1 group of Mn in males, the odds ratio (95 % confidence interval) of NAFLD for tertile 2 and tertile 3 group was 0.82 (0.61,1.10) and 0.64 (0.47,0.87), respectively. The reverse correlation was consistent in patients with different fibrosis severity determined by fibrosis-4 score. The protective association was more evident in those with triglycerides ≥1.7 mmol/L [odds ratio (95 % confidence interval) of tertile 3 vs. tertile 1: 0.40 (0.22,0.75)]. We found a non-significant U-shaped relationship between Mn and NAFLD in women. CONCLUSION: There may exist sex differences for the association between blood Mn and NAFLD. Higher blood Mn may be a potential protective factor for NAFLD in males. The subjects with TG ≥ 1.7 mmol/L would benefit more from higher blood Mn levels.

Association between blood copper and nonalcoholic fatty liver disease according to sex.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is a common disease with potential sex-based difference in the prevalence and prognosis. Copper deficiency may affect the antioxidant defense system and lead to the progression of NAFLD. This study aimed to evaluate the association between blood copper and NAFLD according to sex difference. METHODS: A case-control study of 1816 cases of NAFLD and 1111 sex- and age-matched control cases was conducted in Tangshan, China, from January 1, 2016, to December 31, 2017, based on the Kailuan cohort. In men and women, logistic regression analysis was separately applied to determine the risk of NAFLD, severity of NAFLD based on hepatic steatosis, the NAFLD fibrosis score, and fibrosis-4 score, for each quartile of blood copper with the lowest quartile as the reference. In addition, the effect of metabolic syndrome on the association between copper and NAFLD was assessed. RESULTS: In men, blood copper concentration was lower in the NAFLD group (mean ± SD: 0.617 ± 0.117 µg/mL) than in the control group (mean ± SD: 0.655 ± 0.133 µg/mL) (P < 0.001). After adjustment for possible confounders, the odds ratio of NAFLD at the highest quartile of copper compared to the lowest quartile was 0.57 (95% CI: 0.41-0.80) and the protective effect of higher blood copper was increased with the severity of NAFLD. In the results of stratified analysis, lower copper concentration was a significant additional factor that contributed to higher risk of NAFLD in male subjects with metabolic syndrome. However, no significant association was observed between copper and NAFLD in women with different characteristics, except an NAFLD fibrosis score < -1.455 and moderate hepatic steatosis. CONCLUSIONS: Higher copper levels achieved significant protective effect against NAFLD in men but not in women. Sex-specific intervention is a potential tool for the prevention of development of NAFLD.