Nonalcoholic Fatty Liver Disease without overlapping Metabolic Associated Fatty Liver Disease and the risk of incident type 2 diabetes

Background and aims: re-classifying NAFLD as metabolic-associated fatty liver (MAFLD) has been proposed. While some people fulfil criteria for NAFLD, they do not have MAFLD; and whether NAFLD-only subjects have increased the risk of type 2 diabetes remains unknown. We compared risk of incident T2D in individuals with: (a) NAFLD-only; and (b) MAFLD, to individuals without fatty liver, considering effect modification by sex.Methods: 246 424 Koreans without diabetes or a secondary cause of ultrasound-diagnosed hepatic steatosis were studied. Subjects were stratified into: (a) NAFLD-only status and (b) NAFLD that overlapped with MAFLD (MAFLD). Cox proportional hazards models with incident T2D as the outcome were used to estimate hazard ratios (HRs) for: (a) and (b). Models were adjusted for time-dependent covariates, and effect modification by sex was analysed in subgroups.Results: a total of 5439 participants had NAFLD-only status and 56 839 met MAFLD criteria. During a median follow-up of 5.5 years, 8402 incident cases of T2D occurred. Multivariable-adjusted HRs (95% CI) for incident T2D comparing NAFLD-only and MAFLD to the reference (neither condition) were 2.39 (1.63–3.51) and 5.75 (5.17–6.36) (women), and 1.53 (1.25–1.88) and 2.60 (2.44–2.76) (men), respectively. The increased risk of T2D in the NAFLD-only group was higher in women than in men (p for interaction by sex &lt;0.001) and consistently observed across all subgroups. Risk of T2D was increased in lean participants regardless of metabolic dysregulation (including prediabetes).Conclusions: NAFLD-only participants without metabolic dysregulation and the criteria for MAFLD are at increased risk of developing T2D. This association was consistently stronger in women than in men.<br/

Baseline and change in serum uric acid level over time and resolution of nonalcoholic fatty liver disease in young adults:The Kangbuk Samsung Health Study

Aims: Whether changes in serum uric acid (SUA) are associated with resolution of nonalcoholic fatty liver disease (NAFLD) is uncertain. We aimed to determine the association between (i) baseline SUA and (ii) SUA changes over time, and NAFLD resolution. Materials and Methods: A retrospective cohort study, comprising 38,483 subjects aged &lt;40 years with pre-existing NAFLD, were undertaken. The effects of SUA changes over time were studied in 25,266 subjects. Participants underwent a health examination between 2011 and 2019, and had at least one follow-up liver ultrasound until December 2020. Exposures included baseline SUA levels, and SUA changes between baseline and subsequent visits, categorized into quintiles. The reference group was the third quintile (Q3) containing zero change. The primary endpoint was resolution of NAFLD. Results: During a median follow-up of 4 years, low baseline SUA and decreases in SUA over time, were independently associated with NAFLD resolution (p for trend &lt;0.001). Using SUA as a continuous variable, the likelihood of NAFLD resolution was increased by 10% and 13% in men and women, respectively, per 1 mg/dL decrease in SUA. In a time-dependent model with changes in SUA treated as a time-varying covariate, the aHRs (95%CIs) for NAFLD resolution comparing Q1 (highest decrease) and Q2 (slight decrease) to Q3 (reference) were 1.63 (1.49-1.78) and 1.23 (1.11-1.35) in men and 1.78 (1.49-2.12) and 1.18 (0.95-1.46) in women, respectively. Conclusions: Low baseline SUA levels and a decrease in SUA levels over time were both associated with NAFLD resolution in young adults.<br/

Elevated Serum Gamma-Glutamyltransferase Is a Strong Marker of Insulin Resistance in Obese Children

Elevated levels of serum gamma-glutamyltransferase (GGT) levels have been found to predict the development of type 2 diabetes in adults. The role of GGT in insulin resistance (IR) among children is largely unknown. We investigated whether GGT among hepatic enzymes is independently associated with IR in obese Korean children. A total of 1308 overweight (above the 85th BMI percentile of Korean reference) boys (n=822) and girls (n=486), aged 9–15 years, were studied. Measures acquired included weight, height, percent body fat (BF%), waist circumference, blood pressure, blood glucose and insulin, C-reactive protein, total cholesterol, triglycerides, HDL-Cholesterol, GGT, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). IR was calculated using the homeostasis model assessment (HOMA-IR). Serum GGT and ALT, but not AST, were positively correlated with HOMA-IR in boys (r=0.222 for GGT; P<0.05, r=0.188 for ALT; P<0.05) and girls (r=0.292 for GGT; P<0.05, r=0.258 for ALT; P<0.05). In multiple regression analysis for HOMA-IR as dependent variable, GGT (β=0.068; P=0.053 in boys, β=0.145; P=0.002 in girls) and ALT (β=0.074; P=0.034 in boys, β=0.130; P=0.005 in girls) emerged as determinants of HOMA-IR after adjusting age, BMI, tanner stage, and triglycerides. Serum GGT level is a strong marker of IR in obese Korean children

History of gestational diabetes and incident nonalcoholic fatty liver disease:The Kangbuk Samsung Health Study

Objectives: We examined the relationship between a prior history of gestational diabetes mellitus (pGDM) and risk of incident nonalcoholic fatty liver disease (NAFLD) and investigated the effect of insulin resistance or development of diabetes as mediators of any association.Methods: We performed a retrospective cohort study of 64,397 Korean parous women without NAFLD. The presence of, and the severity of NAFLD at baseline and follow-up were assessed using liver ultrasonography. Cox proportional hazards models were used to determine adjusted hazard ratios (aHRs) for incident NAFLD according to a self-reported GDM history, adjusting for confounders as time-dependent variables. Mediation analyses were performed to examine whether diabetes or insulin resistance may mediate the association between pGDM and incident NAFLD. Results: During a median follow-up of 3.7 years, 6,032 women developed incident NAFLD (of whom 343 had moderate-to-severe NAFLD). Multivariable aHRs (95% confidence intervals) comparing women with time-dependent pGDM to the reference group (no pGDM) was 1.46 (1.33–1.59) and 1.75 (1.25–2.44) for incident overall NAFLD and moderate-to-severe NAFLD, respectively. These associations remained significant in analyses restricted to women with normal fasting glucose Conclusions: A prior history of GDM is an independent risk factor for NAFLD development. Insulin resistance, measured by HOMA-IR, and development of diabetes each explained onl

Self-rated health and risk of incident non-alcoholic fatty liver disease:A cohort study

Although self-rated health (SRH), a subjective measure of overall health status, associates with metabolic abnormalities, studies on the relationship between SRH and non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome, are limited. In this study, we evaluated whether or not SRH predicts the risk of incident NAFLD. This cohort study was performed in a sample of 148,313 Korean adults free of ultrasound-diagnosed NAFLD at baseline with annual or biennial follow-up for a median of 3.7 years. SRH and NAFLD were measured at baseline and follow-up visits. NAFLD was determined based on the ultrasound-diagnosed fatty liver without excessive alcohol consumption or any other cause. Hazard ratios with 95% confidence intervals were estimated via a parametric proportional hazards model. During 522,696.1 person-years of follow-up, 23,855 individuals with new-onset NAFLD were identified (incidence rate, 45.6 per 1,000 person-years). After adjustments for possible confounders including total calorie intake, sleep duration, and depressive symptoms, the multivariate-adjusted hazard ratios (95% confidence intervals) for incident NAFLD comparing good, fair, and poor or very poor SRH to very good SRH were 1.06 (0.97-1.14), 1.18 (1.09-1.27), and 1.24 (1.13-1.37), respectively. This association of SRH with incident NAFLD remained significant after accounting for changes in SRH and confounders during follow-up and was similar across clinically relevant subgroups. In a large-scale cohort study of apparently healthy Korean adults, poor SRH was independently and positively associated with incident NAFLD risk, indicating a predictive role of SRH as a health measure in NAFLD.</p

On Stein's Identity and Near-Optimal Estimation in High-dimensional Index Models

We consider estimating the parametric components of semi-parametric multiple index models in a high-dimensional and non-Gaussian setting. Such models form a rich class of non-linear models with applications to signal processing, machine learning and statistics. Our estimators leverage the score function based first and second-order Stein's identities and do not require the covariates to satisfy Gaussian or elliptical symmetry assumptions common in the literature. Moreover, to handle score functions and responses that are heavy-tailed, our estimators are constructed via carefully thresholding their empirical counterparts. We show that our estimator achieves near-optimal statistical rate of convergence in several settings. We supplement our theoretical results via simulation experiments that confirm the theory

Limaprost and the Risk of Bleeding: A Self-Controlled Case Series Study

Objective To investigate the association between the use of limaprost and the risk of bleeding. Methods A self-controlled case series analysis was conducted using the National Health Insurance Service-National Sample Cohort database in South Korea. We identified patients aged 18 years or older who had at least one prescription of limaprost and were diagnosed with at least one case of bleeding between 2003 and 2019. The incidence rate ratio (IRR) of bleeding was calculated by dividing the incidence rate in the exposed period to limaprost by that in the unexposed period and adjusted for age using conditional Poisson regression model. Results Among 72,860 patients with limaprost prescriptions and bleeding diagnoses, there were 184,732 events of bleeding. After adjusting for age, the IRR was 1.47 (95% confidence interval [CI], 1.43–1.50), wherein the IRR was the highest during the 0–7 days after limaprost initiation (IRR, 2.11; 95% CI, 2.03–2.18). Risk of bleeding was higher when limaprost was concomitantly used with antithrombotics or other drugs for spinal stenosis treatment, and when higher daily doses of limaprost were administered. Conclusion Our findings suggest that the risk of bleeding increased by 1.5-fold in periods of limaprost exposure compared to unexposed periods, with particularly higher risks observed during the first week after limaprost initiation, with concomitant drugs related to bleeding, and with a higher daily dose. A careful risk-benefit assessment is warranted when initiating limaprost, especially when administered with other medications or in higher daily doses

Serum 25-hydroxy vitamin D and the risk of low muscle mass in young and middle-aged Korean adults

Objective: Despite the known benefit of vitamin D in reducing sarcopenia risk in older adults, its effect against muscle loss in the young population is unknown. We aimed to examine the association of serum 25-hydroxy vitamin D [25(OH)D] level and its changes over time with the risk of incident low muscle mass (LMM) in young and middle-aged adults.Design: This study is a cohort study.Methods: The study included Korean adults (median age: 36.9 years) without LMM at baseline followed up for a median of 3.9 years (maximum: 7.3 years). LMM was defined as the appendicular skeletal muscle (ASM) mass by body weight (ASM/weight) of 1 s.d. below the sex-specific mean for the young reference group. Cox proportional hazard models were used to estimate hazard ratios (HRs) with 95% CIs.Results: Of the 192,908 individuals without LMM at baseline, 19,526 developed LMM. After adjusting for potential confounders, the multivariable-adjusted HRs (95% CIs) for incident LMM comparing 25(OH)D levels of 25-&lt;50, 50-&lt;75, and ≥75 nmol/L to 25(OH)D &lt;25 nmol/L were 0.93 (0.90-0.97), 0.85 (0.81-0.89), and 0.77 (0.71-0.83), respectively. The inverse association of 25(OH)D with incident LMM was consistently observed in young (aged &lt;40 years) and older individuals (aged ≥40 years). Individuals with increased 25(OH)D levels (&lt;50-≥50 nmol/L) or persistently adequate 25(OH)D levels (≥50 nmol/L) between baseline and follow-up visit had a lower risk of incident LMM than those with persistently low 25(OH)D levels.Conclusions: Maintaining sufficient serum 25(OH)D could prevent unfavourable changes in muscle mass in both young and middle-aged Korean adults.</p

Potential role of fibrosis-4 score in hepatocellular carcinoma screening:The Kangbuk Samsung Health Study

Aim: Hepatocellular carcinoma (HCC) is a major cause of cancer-related death, with low survival rates worldwide. Fatty liver disease (FLD) significantly contributes to HCC. We studied the screening performance of different methods for identifying HCC in patients with FLD or with metabolic risk factors for FLD.Methods: Korean adults (n=340,825) without a prior HCC diagnosis were categorized into four groups: normal (G1), ≥2 metabolic risk factors (G2), FLD (G3), and viral liver disease or liver cirrhosis (G4). The National Cancer Registry data were used to identify HCC cases within 12 months. We assessed the area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, and positive and negative predictive values of individual or combined screening methods.Results: In 93 HCC cases, 71 were identified in G4, while 20 cases (21.5%) in G2 and G3 combined where ultrasound and fibrosis-4 performed similarly to alpha-fetoprotein and ultrasound. In G2, fibrosis-4 and ultrasound had the highest AUROC (0.93 [0.87–0.99]), whereas in G3, the combined screening methods had the highest AUROC (0.98 [0.95–1.00]). The positive predictive value was lower in G2 and G3 than in G4 but was &gt;5% when restricted to a high fibrosis-4 score.Conclusions: More than 21% of HCC cases were observed in patients with diagnosed FLD or at risk of FLD with metabolic risk factors. Nevertheless, screening for HCC in individuals without cirrhosis or viral hepatitis yielded very low results, despite the potential value of the fibrosis-4 score in identifying individuals at high risk of HCC. KEYWORDS: alpha-fetoprotein, fatty liver disease, fibrosis-4, hepatocellular carcinoma, liver ultrasound<br/