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/

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

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/

Nonalcoholic fatty liver disease and risk of incident young-onset hypertension:effect modification by sex

Background and aims: although nonalcoholic fatty liver disease (NAFLD) and hypertension are increasingly common among young adults, it is uncertain if NAFLD affects incidence of young-onset hypertension, and if the association is modified by sex. We investigated potential effect modification by sex on the association between NAFLD and incident hypertension in young adults (&lt;40 years).Method and results: this cohort study comprised 85,789 women and 67,553 men aged &lt;40 years without hypertension at baseline. Hepatic steatosis was assessed by liver ultrasound and classified as mild or moderate/severe. Hypertension was defined as blood pressure (BP) ≥130/80 mmHg; self-reported history of physician-diagnosed hypertension; or current use of BP-lowering medications. Cox proportional hazard models were used to estimate hazard ratios (HRs; 95% confidence intervals [CIs]) for incident hypertension by NAFLD status (median follow-up 4.5 years). A total of 25,891 participants developed incident hypertension (incidence rates per 103 person-years: 15.6 for women and 63.5 for men). Multivariable-adjusted HRs (95% CIs) for incident hypertension comparing no NAFLD (reference) with mild or moderate/severe NAFLD were 1.68 (1.56–1.80) and 1.83 (1.60–2.09) for women and 1.21 (1.17–1.25) and 1.23 (1.17–1.30) for men, respectively. Stronger associations were consistently observed between NAFLD and incident hypertension in women, regardless of obesity/central obesity (all p-values for interaction by sex &lt;0.001).Conclusions: NAFLD is a potential risk factor for young-onset hypertension with a relatively greater impact in women and in those with more severe hepatic steatosis

Depression and increased risk of nonalcoholic fatty liver disease in individuals with obesity

Aims: the longitudinal relationship between depression and the risk of nonalcoholic fatty liver disease (NAFLD) is uncertain. We examined: a) the association between depressive symptoms and incident hepatic steatosis (HS), both with and without liver fibrosis; and b) the influence of obesity on this association. Methods: cohort of 142,005 Korean adults with neither HS nor excessive alcohol consumption at baseline were followed for up to 8.9 years. The validated Center for Epidemiologic Studies-Depression score (CES-D) was assessed at baseline, and subjects were categorized as non-depressed (a CES-D &lt;8, reference) or depression (CES-D ≥16). HS was diagnosed by ultrasonography. Liver fibrosis was assessed by the fibrosis-4 index (FIB-4). Parametric proportional hazards models were used to estimate the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). Results: during a median follow-up of 4.0 years, 27,810 people with incident HS and 134 with incident HS plus high FIB-4 were identified. Compared with the non-depressed category, the aHR (95% CIs) for incident HS was 1.24 (1.15-1.34) for CES-D ≥16 among obese individuals, and 1.00 (0.95-1.05) for CES-D ≥16 among non-obese individuals (P for interaction with obesity &lt;0.001). The aHR (95% CIs) for developing HS plus high FIB-4 was 3.41 (1.33-8.74) for CES-D≥16 among obese individuals, and 1.22 (0.60-2.47) for CES-D≥16 among non-obese individuals (P for interaction =0.201). Conclusions: depression was associated with an increased risk of incident HS and HS plus high probability of advanced fibrosis, especially among obese individuals

Glycaemic status, insulin resistance, and risk of infection-related mortality:a cohort study

Importance: the impact of non-diabetic hyperglycaemia and insulin resistance on infection-related mortality risk remains unknown.Objective: we investigated the association of glycaemic status and insulin resistance with infection-related mortality in individuals with and without diabetes.Design: cohort study based on Kangbuk Samsung Health Study and national death records.Participants: about 666 888 Korean adults who underwent fasting blood measurements including glucose, glycated haemoglobin (HbA1c), and insulin during health-screening examinations were followed for up to 15.8 years.Main outcome and measures: infection-related mortality, therefore we used Cox proportional hazards regression analyses to estimate hazard ratios (HRs) and 95% CIs for infection-related mortality. Vital status and infection-related mortality were ascertained through national death records. Variable categories were created based on established cut-offs for glucose and HbA1c levels and homeostatic model assessment of insulin resistance (HOMA-IR) quintiles.Results: during a median follow-up of 8.3 years, 313 infectious disease deaths were dentified. The associations of glucose and HbA1c levels with infection-related mortality were J-shaped (P for quadratic trend&lt;.05). The multivariable-adjusted HR (95% CIs) for infection-related mortality comparing glucose levels &lt;5, 5.6-6.9, and ≥7.0 mmol/L to 5.0–5.5 mmol/L (the reference) were 2.31 (1.47–3.64), 1.65 (1.05–2.60), and 3.41 (1.66–7.00), respectively. Among individuals without diabetes, the multivariable-adjusted HR for infection-related mortality for insulin resistance (HOMA-IR ≥75th centile versus &lt;75th centile) was 1.55 (1.04–2.32).Conclusions and relevance: both low and high glycaemic levels and insulin resistance were independently associated with increased infection-related mortality risk, indicating a possible role of abnormal glucose metabolism in increased infection-related mortality.<br/