Metabolic dysfunction-associated fatty liver disease (MAFLD) is a clinical-pathological syndrome primarily characterized by excessive accumulation of fat in hepatocytes, independent of alcohol consumption and other well-established hepatotoxic agents. Mitochondrial dysfunction is widely acknowledged as a pivotal factor in the pathogenesis of various diseases, including cardiovascular diseases, cancer, neurodegenerative disorders, and metabolic diseases such as obesity and obesity-associated MAFLD. Mitochondria are dynamic cellular organelles capable of modifying their functions and structures to accommodate the metabolic demands of cells. In the context of MAFLD, the excess production of reactive oxygen species induces oxidative stress, leading to mitochondrial dysfunction, which subsequently promotes metabolic disorders, fat accumulation, and the infiltration of inflammatory cells in liver and adipose tissue. This review aims to systematically analyze the role of mitochondria-targeted therapies in MAFLD, evaluate current therapeutic strategies, and explore future directions in this rapidly evolving field. We specifically focus on the molecular mechanisms underlying mitochondrial dysfunction, emerging therapeutic approaches, and their clinical implications. This is of significant importance for the development of new therapeutic approaches for these metabolic disorders.

Nonalcoholic fatty liver disease (NAFLD) has rapidly emerged as the most prevalent chronic liver disease globally, representing a significant and escalating public health challenge. Meconopsis integrifolia (Maxim.) Franch, a traditional Tibetan medicinal herb used for treating hepatitis, remains largely unexplored regarding its therapeutic potential and active components in combating NAFLD. This study first evaluated the in vitro lipid accumulation inhibitory activity of different extraction fractions of M. integrifolia using a HepG2 cell steatosis model. The ethyl acetate fraction was found to significantly reduce triglyceride (TG) and low-density lipoprotein (LDL) levels, inhibit lipid droplet deposition in HepG2 cells, and promote lipid metabolism balance through modulation of the AMPK/SREPB-1c/PPAR-α signaling pathway. Further analysis utilizing chromatographic techniques and nuclear magnetic resonance spectroscopy (NMR) led to the isolation of 13 compounds from the active ethyl acetate fraction. Notably, compounds 6, 9, 10, 11, 12, and 13 were identified for the first time from this Tibetan herb. In vitro activity assays and molecular docking analyses further confirmed that the compounds Luteolin (1), Quercetin 3-O-[2‴, 6‴-O-diacetyl-β-d-glucopyranosyl-(1→6)-β-d-glucopyranoside] (6), and Quercetin 3-O-[2‴-O-acetyl-β-d-glucopyranosyl-(1→6)-β-d-glucopyranoside] (8) are potential key components responsible for the NAFLD-ameliorating effects of M. integrifolia. This study highlights the therapeutic potential of M. integrifolia in treating NAFLD and provides a foundation for its further development and application, underscoring its significance in the advanced utilization of traditional Tibetan medicine.

Glycogenic hepatopathy is associated with significant psychosocial consequences and health costs. Metabolic Dysfunction-Associated Steatotic Liver Disease and glycogenic hepatopathy are frequently confused as "fatty liver" when seen on ultrasonography. We wished to examine liver fat and glycogen content in groups defined based on metabolic and liver disease phenotypes.

This case-control study undertaken in a tertiary hospital used nuclear proton magnetic resonance spectroscopy (1H-MRS) to examine liver fat and glycogen content in five clinical groups, each containing five participants: 1. type 1 diabetes with glycogenic hepatopathy, 2. satisfactorily controlled type 1 diabetes with no liver disease, 3. poorly controlled type 1 diabetes without liver disease, 4. a control group of body mass index- and age-matched individuals without diabetes or liver disease, and 5. hepatic steatosis.

Fat content was highest in the hepatic steatosis (median 15.4 %, IQR 10.0-19.3) and glycogenic hepatopathy (median 6.5 %, IQR 4.5-9.1) groups and compared to both of these groups was lower in the control group (median 1.0 %, IQR 0.7-1.1, p 0.002 and 0.022), the T1DM group with satisfactory control (median 0.3 %, IQR 0.2-0.6, p < 0.001 and <0.001), and the T1DM group with poor control without liver disease (median 1.1 %, IQR 0.9-1.1, p 0.001 and 0.012). No participants from the type 1 diabetes poor control, type 1 diabetes satisfactory control or the no diabetes groups had 1H-MRS-diagnosed hepatic steatosis. 1H-MRS glycogen content could not be interpreted in the majority of those with glycogenic hepatopathy because of interference from the fat signal.

In cases diagnosed with glycogenic hepatopathy there may be significant concomitant fat accumulation, compounding the already elevated cardiovascular risk in this cohort. The technique of 1H-MRS has not been demonstrated to be useful for diagnosing glycogenic hepatopathy.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multisystem condition destined to become pandemic in the coming decades. This study aimed at evaluating the economic impact of MASLD in the Italian population from the Italian National Healthcare Service (NHS) perspective.

The economic impact of the MASLD was assessed by developing a calculation model in Microsoft Excel® from the Italian NHS perspective, considering healthcare resources and direct costs. The target population was based on the prevalence data. Through a literature search, complications of MASLD were identified, including MASH, with relative risk of evolution into CC, DCC, HCC, T2DM, cardiovascular diseases, in particular AMI and stroke, CKD, and CRC. The differential impact between complication development in the population with MASLD and the same sample size population without-MASLD was evaluated. Differential risk data, mortality rates, and event unit costs were drawn from the published international literature. Frequency and cost data were applied to the total target population, the total annual costs and mortality data, referring to the two arms, were then calculated, and the differential value was obtained.

Based on an estimated 11,546,370 MASLD target population, an annual illness impact of €12,251,631,822 was calculated, corresponding to a difference of €7,731,674,054 compared with the same sample size without MASLD. Moreover, the MASLD population is expected to experience 13,438 additional deaths annually.

The growing epidemiological impact of MASLD and its complications represent a huge economic burden for healthcare services worldwide. An integrated approach, including changes in lifestyle behaviors, will be the first step. Specific drugs for MASLD are not yet available; however, studies are underway, and combined pharmaceutical therapies may be an inevitable choice to achieve adequate control of MASLD and its complications.

Obesity poses a significant and growing risk factor for chronic kidney disease (CKD), requiring comprehensive evaluation and management strategies. This review explores the intricate relationship between obesity and CKD, emphasizing the diverse phenotypes of obesity, including sarcopenic obesity and metabolically healthy versus unhealthy obesity, and their differential impact on kidney function. We discuss the epidemiological evidence linking elevated body mass index (BMI) with CKD risk while also addressing the paradoxical survival benefits observed in obese CKD patients. Various measures of obesity, such as BMI, waist circumference, and visceral fat assessment, are evaluated in the context of CKD progression and outcomes. Mechanistic insights into how obesity promotes renal dysfunction through lipid metabolism, inflammation, and altered renal hemodynamics are elucidated, underscoring the role of adipokines and the renin-angiotensin-aldosterone system. Furthermore, the review examines current strategies for assessing kidney function in obese individuals, including the strengths and limitations of filtration markers and predictive equations. The management of obesity and associated comorbidities like arterial hypertension, type 2 diabetes mellitus, and non-alcoholic fatty liver disease in CKD patients is discussed. Finally, gaps in the current literature and future research directions aimed at optimizing the management of obesity-related CKD are highlighted, emphasizing the need for personalized therapeutic approaches to mitigate the growing burden of this intertwined epidemic.

Albuminuria is considered an early and sensitive marker of kidney dysfunction, but also an independent cardiovascular risk factor. Considering the possible relationship among metabolic liver disease, cardiovascular disease and chronic kidney disease, we aimed to evaluate the risk of developing albuminuria regarding the presence of epicardial adipose tissue and the steatotic liver disease status.

A retrospective long-term longitudinal study including 181 patients was carried out. Epicardial adipose tissue and steatotic liver disease were assessed by computed tomography. The presence of albuminuria at follow-up was defined as the outcome.

After a median follow up of 11.2 years, steatotic liver disease (HR 3.15; 95% CI, 1.20-8.26; p = 0.02) and excess amount of epicardial adipose tissue (HR 6.12; 95% CI, 1.69-22.19; p = 0.006) were associated with an increased risk of albuminuria after adjustment for visceral adipose tissue, sex, age, weight status, type 2 diabetes, prediabetes, hypertriglyceridemia, hypercholesterolemia, arterial hypertension, and cardiovascular prevention treatment at baseline. The presence of both conditions was associated with a higher risk of developing albuminuria compared to having steatotic liver disease alone (HR 5.91; 95% CI 1.15-30.41, p = 0.033). Compared with the first tertile of visceral adipose tissue, the proportion of subjects with liver steatosis and abnormal epicardial adipose tissue was significantly higher in the second and third tertile. We found a significant correlation between epicardial fat and steatotic liver disease (rho = 0.43 [p < 0.001]).

Identification and management/decrease of excess adiposity must be a target in the primary and secondary prevention of chronic kidney disease development and progression. Visceral adiposity assessment may be an adequate target in the daily clinical setting. Moreover, epicardial adipose tissue and steatotic liver disease assessment may aid in the primary prevention of renal dysfunction.

Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in children and adolescents, particularly those with obesity. NAFLD is considered a hepatic manifestation of the metabolic syndrome due to its close associations with abdominal obesity, insulin resistance, and atherogenic dyslipidemia. Experts have proposed an alternative terminology, metabolic dysfunction-associated fatty liver disease (MAFLD), to better reflect its pathophysiology. This study aimed to develop consensus statements and recommendations for pediatric MAFLD through collaboration among international experts.

A group of 65 experts from 35 countries and six continents, including pediatricians, hepatologists, and endocrinologists, participated in a consensus development process. The process encompassed various aspects of pediatric MAFLD, including epidemiology, mechanisms, screening, and management.

In round 1, we received 65 surveys from 35 countries and analyzed these results, which informed us that 73.3% of respondents agreed with 20 draft statements while 23.8% agreed somewhat. The mean percentage of agreement or somewhat agreement increased to 80.85% and 15.75%, respectively, in round 2. The final statements covered a wide range of topics related to epidemiology, pathophysiology, and strategies for screening and managing pediatric MAFLD.

The consensus statements and recommendations developed by an international expert panel serve to optimize clinical outcomes and improve the quality of life for children and adolescents with MAFLD. These findings emphasize the need for standardized approaches in diagnosing and treating pediatric MAFLD.

This work was funded by the National Natural Science Foundation of China (82070588, 82370577), the National Key R&D Program of China (2023YFA1800801), National High Level Hospital Clinical Research Funding (2022-PUMCH-C-014), the Wuxi Taihu Talent Plan (DJTD202106), and the Medical Key Discipline Program of Wuxi Health Commission (ZDXK2021007).

The aim of the study was to evaluate the effects of tofogliflozin, a selective sodium-glucose cotransporter 2 inhibitor, on circulating levels of hepatic enzymes, uric acid and hemoglobin levels in patients with type 2 diabetes mellitus (T2DM).

We evaluated longitudinal changes in circulating aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-GTP), uric acid, and hemoglobin levels in tofogliflozin (n = 169) and conventional treatment groups (n = 170) using data obtained from the UTOPIA trial, a randomized prospective study conducted to evaluate the efficacy of tofogliflozin in preventing atherosclerosis.

Within 104 weeks, tofogliflozin treatment, but not conventional treatment, significantly reduced AST, ALT, and γ-GTP levels. This reduction was significantly greater in the tofogliflozin group than in the conventional group. Stratified analysis showed that, in patients with obesity (defined as body mass index (BMI) ≥ 25.0 kg/m2), significant differences were observed in AST, ALT, and γ-GTP changes from baseline to 104 weeks between treatment groups. However, in patients without obesity, there were no significant differences in AST and γ-GTP changes from baseline to 104 weeks between treatment groups. Multivariable regression analysis showed that changes in BMI and HbA1c levels were independently associated with changes in AST, ALT, and γ-GTP levels. The reduction of uric acid and the increase of hemoglobin from baseline to 104 weeks were significantly greater in the tofogliflozin group than in the conventional group.

The beneficial effects of tofogliflozin on circulating levels of hepatic enzymes, uric acid, and Hb lasted for 2 years in patients with T2DM.

UMIN000017607 (https://www.umin.ac.jp/icdr/index.html).

The online version contains supplementary material available at 10.1007/s13340-024-00693-x.

Metabolic Dysfunction-Associated Fatty Liver Disease and Diabetes Mellitus are two prevalent metabolic disorders that often coexist and synergistically contribute to the progression of each other. Several pathophysiological pathways are involved in the association, including insulin resistance, inflammation, and lipotoxicity, providing a foundation for understanding the complex interrelationships between these conditions. The presence of MASLD has a significant impact on diabetes risk and the development of microvascular and macrovascular complications, and diabetes significantly contributes to an increased risk of liver fibrosis progression in MASLD and the development of hepatocellular carcinoma. Moreover, both pathologies have a synergistic effect on cardiovascular events and mortality. Therapeutic interventions targeting MASLD and diabetes are discussed, considering lifestyle modifications, pharmacological agents, and emerging treatment modalities. The review also addresses the challenges in managing these comorbidities, such as the need for personalized approaches and the potential impact on cardiovascular health. The insights gleaned from this analysis can inform clinicians, researchers, and policymakers in developing integrated strategies for preventing, diagnosing, and managing these metabolic disorders.

Metabolic-associated fatty liver disease (MAFLD) is the most common chronic liver disease observed in clinical practice worldwide. This disorder has been independently associated with an increased risk of developing chronic kidney disease (CKD). The aim of this study was to evaluate whether a 2-year intervention based on a Mediterranean diet (MedDiet) and physical activity focussed on reducing intrahepatic fat contents (IFC) was associated with a decreased risk of CKD. Forty adults (50% women) residing in Mallorca, aged 48 to 60 years, diagnosed with MAFLD were recruited. Participants were divided into two groups based on whether they improved IFC measured by nuclear magnetic resonance. Anthropometric and clinical parameters improved in responders, including reduced weight, body mass index (BMI), and waist circumference. Only responders showed improvements in lipid profile and liver enzymes. Haematological parameters showed favourable changes in both groups. Oxidative stress and inflammatory biomarkers differed between groups. Responders had lower plasma interleukine-18 (IL-18) levels, but higher erythrocyte malonaldehyde (MDA) levels. Non-responders showed increased erythrocyte catalase and superoxide dismutase activity. After 2 years, non-responders had higher serum creatinine, Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) levels, while responders showed reductions in these parameters together with uric acid and urine albumin-to-creatinine ratio (UACR). Positive correlations were found between changes in IFC and kidney injury biomarkers, including MDRD and serum creatinine levels. In conclusion, a healthy diet based on the Mediterranean dietary pattern and lifestyle promotes significant improvements in parameters related to cardiovascular, hepatic, and renal health.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease worldwide, paralleling the rising pandemic of obesity and type 2 diabetes. Due to the growing global health burden and complex pathogenesis of MASLD, a multifaceted and innovative therapeutic approach is needed. Incretin receptor agonists, which were initially developed for diabetes management, have emerged as promising candidates for MASLD treatment. This review describes the pathophysiological mechanisms and action sites of three major classes of incretin/glucagon receptor agonists: glucagon-like peptide-1 receptor agonists, glucose-dependent insulinotropic polypeptide receptor agonists, and glucagon receptor agonists. Incretins and glucagon directly or indirectly impact various organs, including the liver, brain, pancreas, gastrointestinal tract, and adipose tissue. Thus, these agents significantly improve glycemic control and weight management and mitigate MASLD pathogenesis. Importantly, this study provides a summary of clinical trials analyzing the effectiveness and safety of incretin receptor agonists in MASLD management and provides an in-depth analysis highlighting their beneficial effects on improving liver function, hepatic steatosis, and intrahepatic inflammation. There are emerging challenges associated with the use of these medications in the real world, particularly adverse events, drug-drug interactions, and barriers to access, which are discussed in detail. Additionally, this review highlights the evolving role of incretin receptor agonists in MASLD management and suggests future research directions.

Cardiovascular, renal and metabolic (CaReMe) diseases are individually among the leading global causes of death, and each is associated with substantial morbidity and mortality. However, as these conditions commonly coexist in the same patient, the individual risk of mortality and morbidity is further compounded, leading to a considerable healthcare burden. A number of pathophysiological pathways are common to diseases of the CaReMe spectrum, including neurohormonal dysfunction, visceral adiposity and insulin resistance, oxidative stress and systemic inflammation. Because of the shared pathology and common co-occurrence of the CaReMe diseases, the value of managing these conditions holistically is increasingly being realized. A number of pharmacological and non-pharmacological approaches have been shown to offer simultaneous metabolic, cardioprotective and renoprotective benefits, leading to improved patient outcomes across the CaReMe spectrum. In addition, increasing value is being placed on interdisciplinary team-based and coordinated care models built on greater integration between specialties to increase the rate of early diagnosis and adherence to practice guidelines, and improve clinical outcomes. This interdisciplinary approach also facilitates integration between primary and specialty care, improving the patient experience, optimizing resources, and leading to efficiencies and cost savings. As the burden of CaReMe diseases continues to increase, implementation of innovative and integrated care delivery models will be essential to achieve effective and efficient chronic disease management and to ensure that patients benefit from the best care available across all three disciplines.

The systematic review aimed to assess the risks of metabolic dysfunction-associated steatotic liver disease (MASLD) on all-cause and cause-specific mortality in patients with type 2 diabetes (T2DM). EMBASE and MEDLINE were searched from inception to June 2022 for observational studies examining the relationship between MASLD and the risk of mortality among T2DM patients. Meta-analysis was conducted using random-effects models with hazard ratios (HRs) to quantify the risk of mortality. A total of 5877 articles were screened, and ultimately, 12 eligible studies encompassing 368 528 T2DM patients, with a median follow-up of 8.9 years (interquartile range, 4.7-14.5), were included. Our analysis revealed a significant association between MASLD and an increased risk of all-cause mortality in T2DM patients [HR 1.28; 95% confidence interval (CI), 1.05-1.58; I 2  = 90%]. Meta-regression analyses did not show significant effects of mean age, mean BMI, and percentage of smokers, hypertension, and hyperlipidemia on the association between MASLD and the risk of all-cause mortality. However, we found that MASLD was not significantly associated with mortality related to cardiovascular diseases (HR 1.05; 95% CI, 0.82-1.35; I2  = 0%) or cancer (HR 1.21; 95% CI, 0.41-3.51; I 2  = 79%) among patients with T2DM. No publication bias was observed. This comprehensive meta-analysis provides substantial evidence supporting a significant association between MASLD and an increased risk of all-cause mortality among the T2DM population. These findings underscore the potential benefits of screening for MASLD in T2DM patients, aiding in the early identification of high-risk individuals and enabling risk modification strategies to improve survival.

There is increasing appreciation of the complex interaction between nonalcoholic fatty liver disease (NAFLD) with type 2 diabetes (T2D) and insulin resistance. Not only is the prevalence of NAFLD disease high among patients with T2D, the liver disease is also more progressive. Currently, the global prevalence of NAFLD in the general population (2016-2019) is 38 %. The prevalence of T2D among those with NAFLD is approximately 23 % while the prevalence of NAFLD among those with T2D can be as high as 70 %. The prevalence of nonalcoholic steatohepatitis (NASH) is approximately 7 % in the general population and 37 % among patients with T2D. Globally, the MENA and Latin America regions of the world appear to have the highest burden of both NAFLD and T2D. Compared to those with NAFLD but without T2D, those with NAFLD and T2D are at a much higher risk for disease progression to cirrhosis and for decompensated cirrhosis, hepatocellular carcinoma, and all-cause mortality. Given that highly effective new treatments are available for T2D, high risk NAFLD with T2D should be considered for these regimens. This requires implementation of risk stratification algorithms in the primary care and endocrinology practices to identify those patients at highest risk for adverse outcomes.

(1) Background: The relationship between nonalcoholic fatty liver disease (NAFLD) and incident chronic kidney disease (CKD) is unclear, and long-term follow-up data are limited. Therefore, this study aimed to evaluate whether NAFLD, as assessed by the fatty liver index (FLI), could predict the development of CKD in a community-based Korean cohort over 16 years. (2) Methods: Among the 10,030 total participants, 7778 patients without CKD were selected from the Korean Genome and Epidemiology Study (KoGES). The FLI grade ranged from 0 to 100 and was divided into three groups: low (FLI, <30), intermediate (FLI, 30-59), and high (FLI, ≥60). An estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 or the development of proteinuria was considered to indicate incident CKD. (3) Results: During the 16-year follow-up period, 919 individuals (11.8%) developed CKD. The HRs of incident CKD in the intermediate FLI group (30-59) and high FLI group (≥60) increased compared with the reference low FLI group (<30) after adjusting for potentially confounding variables. NAFLD, as assessed by the FLI, was an independent risk factor for CKD. (4) Conclusions: Our findings suggest that the FLI, a simple surrogate biomarker of fatty liver disease, may be used to identify people at high risk of incident CKD in clinical practice.

The progression of metabolic dysfunction-associated steatotic liver disease (MASLD) has been found to manifest in a series of hepatic and extrahepatic complications. A comprehensive meta-analysis of the longitudinal outcomes associated with MASLD has yet to be conducted.

To investigate the longitudinal outcomes associated with MASLD, Medline and Embase databases were searched to identify original studies that evaluated the longitudinal risks of incident clinical outcomes among MASLD patients compared with non-MASLD individuals. DerSimonian Laird random-effects meta-analysis was performed. Pooled effect estimates were calculated, and heterogeneity among studies was evaluated.

One hundred twenty-nine studies were included in the meta-analysis. Meta-analysis revealed a significant increase in the risk of cardiovascular outcomes (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.27-1.60; P < .01), various metabolic outcomes such as incident hypertension (HR, 1.75; 95% CI, 1.46-2.08; P < .01), diabetes (HR, 2.56; 95% CI, 2.10-3.13; P < .01), pre-diabetes (HR, 1.69; 95% CI, 1.22-2.35; P < .01), metabolic syndrome (HR, 2.57; 95% CI, 1.13-5.85; P = .02), chronic kidney disease (HR, 1.38; 95% CI, 1.27-1.50; P < .01), as well as all cancers (HR, 1.54; 95% CI, 1.35-1.76; P < .01) among MASLD patients compared with non-MASLD individuals. By subgroup analysis, MASLD patients with advanced liver disease (HR, 3.60; 95% CI, 2.10-6.18; P < .01) were also found to be associated with a significantly greater risk (P = .02) of incident diabetes than those with less severe MASLD (HR, 1.63; 95% CI, 1.0-2.45; P = .02) when compared with non-MASLD.

The present study emphasizes the association between MASLD and its clinical outcomes including cardiovascular, metabolic, oncologic, and other outcomes. The multisystemic nature of MASLD found in this analysis requires treatment targets to reduce systemic events and end organ complications.

Nonalcoholic fatty liver disease or metabolic-associated fatty liver disease (MAFLD) is a common condicion with increasing prevalence and incidence, specially in patients with type 2 diabetes mellitus (T2DM). Both cardiovascular and renal disease are clearly increased in these patients, particularly in those with diabetic nephropathy. In the liver-heart-kidney-metabolic axis, the common pathophysiological basis of MAFLD, cardiovascular disease (CVD), chronic kidney disease (CKD), and T2DM is the same. The clinical relationship between all of them is clear and is multidirectional: MAFLD may precede the development of cardiovascular and renal disease, and may also worsen the prognosis of these complications once developed. In this review we emphasize the importance of targeting MAFLD in Diabetic kidney disease, with the goal of detecting high-risk patients in order to improve their prognosis.

Fatty liver index (FLI) was developed as a simple and accurate marker of hepatic steatosis. FLI is derived from an algorithm based on body mass index, waist circumference, and levels of triglycerides and gamma-glutamyltransferase, and it is widely used in clinical and epidemiological studies as a screening tool for discriminating between healthy and nonalcoholic fatty liver disease (NAFLD) subjects. However, a systematic review of the literature regarding FLI revealed that this index has more extensive relationships with biochemical and physiological parameters. FLI is associated with key parameters of lipid, protein and carbohydrate metabolism, hormones, vitamins and markers of inflammation, or oxidative stress. FLI can be a predictor or risk factor for a number of metabolic and nonmetabolic diseases and mortality. FLI is also used as an indicator for determining the effects of health-related prevention interventions, medications, and toxic substances on humans. Although in most cases, the exact mechanisms underlying these associations have not been fully elucidated, they are most often assumed to be mediated by insulin resistance, inflammation, and oxidative stress. Thus, FLI may be a promising marker of metabolic health due to its multiple associations with parameters of physiological and pathological processes. In this context, the present review summarizes the data from currently available literature on the associations between FLI and biochemical variables and physiological functions. We believe that this review will be of interest to researchers working in this area and can provide new perspectives and directions for future studies on FLI.

To investigate the effects of metabolic associated fatty liver disease (MAFLD) on chronic kidney disease (CKD) and abnormal albuminuria and the interaction between MAFLD and diabetes on abnormal albuminuria.

Data of participants in the American 2017-2018 National Health and Nutrition Examination Survey were analyzed. Hepatic steatosis was defined as median controlled attenuation parameter ≥248 dB/m, which was measured by ultrasound transient elastography. MAFLD was defined by evidence of hepatic steatosis on ultrasound in addition to any metabolic dysregulation. Hepatic fibrosis was detected by FibroScan and quantified by parameter of stiffness (E). Hepatic fibrosis was defined as E ≥ 9.7 kPa. As component of CKD, reduced estimated glomerular filtration rate (eGFR) was defined as<60 mL/min/1.73 m2 and abnormal albuminuria was defined as urinary albumin-to-creatinine ratio ≥ 30 mg/g.

Data pertaining to 5119 participants were included in the analysis, with 40.6% hepatic normal, 52.1% MAFLD, and 7.2% hepatic fibrosis. Multivariable regression analyses showed that for abnormal albuminuria, the odds ratio (OR) was 0.82 (0.65-1.04) for MAFLD group and 1.73 (1.14.-,2.63) for hepatic fibrosis group, both taking the hepatic healthy group as reference. As for reduced eGFR, the OR was 0.68 (0.51-0.92) for MAFLD group and 0.93 (0.56-1.53) for hepatic fibrosis group. Diabetes was significantly related to greater risk of abnormal albuminuria (3.04 [2.70-3.42]) and reduced eGFR (1.53 [1.33-1.77]). With regard to the prevalence of abnormal albuminuria, the OR was 1.64 (1.03-2.60) for those with hepatic fibrosis only, 3.30 (2.80-3.89) for those with diabetes only, and 5.05 (3.30-7.72) for those with both two conditions. But there were neither additive interaction (relative excess risk due to interaction 0.56 [-1.41-.53], p = .577) nor multiplicative interaction (OR 0.81 [0.45-1.47], p = .492) between hepatic fibrosis and diabetes on the prevalence of abnormal albuminuria.

MAFLD with hepatic fibrosis is an independent risk factor for abnormal albuminuria, but it does not have interaction with diabetes on abnormal albuminuria.

We investigated whether higher fibrotic burden was independently associated with poorer kidney outcomes in patients with hepatitis B virus (HBV)-related cirrhosis.

A total of 1691 patients with radiologically diagnosed HBV-related cirrhosis but without baseline chronic kidney disease (CKD) who underwent transient elastography (TE) between March 2012 and August 2018 were selected. The study outcome was the composite of development of incident CKD, defined as the occurrence of estimated glomerular filtration rate (eGFR) <60 mL/minute/1.73 m2 or proteinuria (≥1+ on dipstick test) on 2 consecutive measurements during follow-up, 50% decline in eGFR or onset of end-stage kidney disease (initiation of chronic dialysis), or all-cause mortality.

The mean age was 53.4 years and 1030 (60.9%) patients were male. During 8379 person-years of follow-up (median 5.2 years), 60 (3.5%) patients experienced study outcomes. When stratified according to TE-defined fibrotic burden, multivariable Cox models revealed that risk of poorer kidney outcomes was 2.77-fold (95% confidence interval, 1.16-6.63; P < .001) higher in patients with liver stiffness range indicating cirrhosis (≥11.7 kPa), compared to those without significant liver fibrosis (<7.9 kPa). These associations remained significant even after adjusting for vigorous confounders.

Higher fibrotic burden assessed using TE was independently associated with poorer kidney outcomes in patients with HBV-related cirrhosis.

Cardiometabolic disease (CMD), which encompasses metabolic-associated fatty liver disease (MAFLD), chronic kidney disease (CKD) and cardiovascular disease (CVD), has been increasing considerably in the past 50 years. CMD is a complex disease that can be influenced by genetics and environmental factors such as diet. With the increased reliance on processed foods containing saturated fats, fructose and cholesterol, a mechanistic understanding of how these molecules cause metabolic disease is required. A major pathway by which excessive nutrients contribute to CMD is through oxidative stress. In this review, we discuss how oxidative stress can drive CMD and the role of aberrant nutrient metabolism and genetic risk factors and how they potentially interact to promote progression of MAFLD, CVD and CKD. This review will focus on genetic mutations that are known to alter nutrient metabolism. We discuss the major genetic risk factors for MAFLD, which include Patatin-like phospholipase domain-containing protein 3 (PNPLA3), Membrane Bound O-Acyltransferase Domain Containing 7 (MBOAT7) and Transmembrane 6 Superfamily Member 2 (TM6SF2). In addition, mutations that prevent nutrient uptake cause hypercholesterolemia that contributes to CVD. We also discuss the mechanisms by which MAFLD, CKD and CVD are mutually associated with one another. In addition, some of the genetic risk factors which are associated with MAFLD and CVD are also associated with CKD, while some genetic risk factors seem to dissociate one disease from the other. Through a better understanding of the causative effect of genetic mutations in CMD and how aberrant nutrient metabolism intersects with our genetics, novel therapies and precision approaches can be developed for treating CMD.

Previous studies have highlighted changes in the cerebral cortical structure and cognitive function among nonalcoholic fatty liver disease (NAFLD) patients. However, the impact of NAFLD on cerebral cortical structure and specific affected brain regions remains unclear. Therefore, we aimed to explore the potential causal relationship between NAFLD and cerebral cortical structure.

We conducted a Mendelian randomization (MR) study using genetic predictors of alanine aminotransferase (ALT), NAFLD, and percent liver fat (PLF) and combined them with genome-wide association study (GWAS) summary statistics from the ENIGMA Consortium. Several methods were used to assess the effect of NAFLD on full cortex and specific brain regions, along with sensitivity analyses.

At the global level, PLF nominally decreased SA of full cortex; at the functional level, ALT presented a nominal association with reduced SA of parahippocampal gyrus, TH of pars opercularis, TH of pars orbitalis, and TH of pericalcarine cortex. Besides, NAFLD presented a nominal association with reduced SA of parahippocampal gyrus, TH of pars opercularis, TH of pars triangularis and TH of pericalcarine cortex, but increased TH of entorhinal cortex, lateral orbitofrontal cortex and temporal pole. Furthermore, PLF presented a nominal association with reduced SA of parahippocampal gyrus, TH of pars opercularis, TH of cuneus and lingual gyrus, but increased TH of entorhinal cortex.

NAFLD is suggestively associated with atrophy in specific functional regions of the human brain.

Glomerular hyperfiltration (GH) is an increase in the glomerular filtration rate, possibly progressing to chronic kidney disease (CKD). Metabolic-associated steatotic liver disease (MASLD) is linked to an increased risk of CKD, especially if fibrosis is present; however, the association between GH and MASLD has not been explored. To evaluate GH prevalence in MASLD and its possible correlation with liver fibrosis. 772 consecutive patients with ultrasound MASLD (mean age 47.3 ± 8.9 years, 67.1% males) were enrolled. GH was defined as estimated glomerular filtration rate (eGFR) greater than the upper quartile of values in the cohort. Liver stiffness measurement (LSM) by FibroScan ≥ 7.2 kPa suggested liver fibrosis. GH was present in 20% of patients, liver fibrosis in 30%. In total, 53.4% of the cohort was obese, 40.9% hypertensive, 36.3% diabetic and 70.8% dyslipidaemic. GH patients compared to non-GH were significantly younger (38.4 ± 8.3 vs. 49.5 ± 7.7, p < 0.001), with higher prevalence of LSM > 7.2 kPa (35.5% vs. 29%, p < 0.001), without any difference in metabolic comorbidities. In multivariate analysis, age (OR 0.85, CI 95% 0.82-0.87) and significant fibrosis (OR 1.83; CI 95%1.10-3.03) remained independently associated with GH, regardless of the presence of metabolic alterations and nephrotoxic drugs. GH, an early marker of renal damage, is highly prevalent in MASLD and is associated with hepatic fibrosis. GH may be considered an early marker of both liver and renal disease and its recognition could prompt the management of risk factors aimed at preventing the progression of both hepatic and renal disease.

Nonalcoholic fatty liver disease (NAFLD) and advanced hepatic fibrosis (AHF) have been associated with sarcopenia. However, modifiers of this association have been less studied.

This study used data from the NHANES database 2011-2014 of the USA. Adults aged 18 years or older, had complete information of handgrip strength test and NAFLD and AHF status were eligible for inclusion. NAFLD was defined using the Fatty Liver Index (FLI). AHF was defined using the NAFLD fibrosis score (NFS). Univariate and multivariate logistic regression were performed to determine the associations between the study variables and prevalent NAFLD and AHF.

A total of 19 931 participants were selected from the 2011-2014 NHANES database. The multivariate analysis showed that stronger grip strength was significantly and independently associated with decreased odds for NAFLD (tertile 2: adjusted odd ratio [aOR]: 0.41, 95% confidence interval [CI]: 0.29-0.59; tertile 3: aOR: 0.11, 95% CI: 0.05-0.24) and AHF (tertile 2: aOR: 0.66, 95% CI: 0.46-0.94; tertile 3: aOR: 0.28, 95% CI: 0.12-0.63). In stratified analyses, strongest grip strength was significantly associated with reduced odds for NAFLD regardless of age, body mass index, and having diabetes or not. Strongest grip strength was associated with reduced odds for NAFLD in individuals who had moderate to ideal physical activity (aOR: 0.31).

Grip strength has an inverse association with prevalent NAFLD and AHF in the US population, which appears to be modified by physical activity level. Future prospective cohort studies are needed to clarify the role of physical activity in modifying the risks.

For the first time in nearly half a century, fatty liver disease has undergone a change in name and definition, from the exclusive term, non-alcoholic fatty liver disease (NAFLD), to the inclusion-based, metabolic-associated fatty liver disease (MAFLD). This has led investigators across the globe to evaluate the impact the nomenclature change has had on the epidemiology and natural history of the disease.

This systematic review provides a comprehensive overview on how the shift in name and diagnostic criteria has influenced point prevalence in different geographic regions, as well as morbidity and mortality risk, whilst highlighting gaps in the literature that need to be addressed.

MAFLD prevalence is higher than NAFLD prevalence, carries a higher risk of overall mortality, with greater granularity in risk-stratification amongst MAFLD subtypes.

Nonalcoholic fatty liver disease (NAFLD), sarcopenia and sarcopenic obesity (SO) are highly prevalent conditions that may coexist, especially in the aging population, without any approved pharmacologic treatment for all of them. There are multiple pathophysiologic mechanisms suggested to explain an association between NAFLD and sarcopenia or SO, including alterations in the adipokines, cytokines, hepatokines and myokines, which may interplay with other factors, such as aging, diet and physical inactivity. In clinical terms, most observational studies support an association between NAFLD and sarcopenia or SO; importantly, there are few cohort studies indicating higher mortality in patients with NAFLD and sarcopenia. Their association also bears some treatment considerations: for example, pioglitazone or vitamin E, suggested as off label treatment for selected patients with nonalcoholic steatohepatitis, may be recommended in the coexistence of sarcopenia or SO, since limited evidence did not show adverse effects of them on sarcopenia and abdominal obesity. In this review, evidence linking sarcopenia and SO with NAFLD is summarized, with a special focus on clinical data. A synopsis of the major pathophysiological links between NAFLD and sarcopenia/SO is initially presented, followed by selected clinical studies and, finally, treatment considerations in patients with NAFLD and sarcopenia or SO are discussed.

The liver plays an important role in normal metabolism and physiological functions such as acid-base balance; however, limited epidemiologic studies have investigated how the liver contributes toward acid-base balance using non-invasive biomarkers. We determined associations between serum biomarkers related to acid-base balance and renal function with liver CYP1A2 activity. We used data from 1381 participants of the 2009-2010 National Health and Nutrition Examination Survey (NHANES) with measurements of serum phosphorus, serum bicarbonate, caffeine intake, caffeine metabolites, and estimated glomerular filtration rate (eGFR). Liver CYP1A2 activity was estimated using urine caffeine metabolite indices, which were calculated as the ratio of one of the urine caffeine metabolites (i.e., paraxanthine and 1-methyluric acid) to caffeine intake. We analyzed associations in the whole data set and in different strata of hepatic steatosis index (HSI) based on different cut-points. We found that serum bicarbonate was positively associated with CYP1A2 activity in the whole data set when comparing persons with bicarbonate at Q4 to Q1 (β = 0.18, p = 0.10 for paraxanthine; β = 0.20, p = 0.02 for 1-methyluric acid). Furthermore, serum phosphorus was positively associated with CYP1A2 activity only in the stratum of 30 ≤ HSI < 36. Lastly, low eGFR was significantly associated with lower CYP1A2 activity measured with paraxanthine in the whole dataset and in all the strata with HSI < 42; when comparing eGFR < 60 to eGFR > 90, β estimates ranged from -0.41 to -1.38, p-values ranged from 0.0018 to 0.004. We observed an opposite trend in the highest stratum (HSI ≥ 42). Non-invasive measurements of serum bicarbonate, serum phosphorus, and eGFR have dynamic associations with CYP1A2 activity. These associations depend on the extent of liver damage and the caffeine metabolite used to assess CYP1A2 activity.

In Australia, the overall prevalence of liver disease is increasing. Maximising uptake of community screening programmes by understanding patient preferences is integral to developing consumer-centred care models for liver disease. Discrete choice experiments (DCEs) are widely used to elicit preferences for various healthcare services. Attribute development is a vital component of a well-designed DCE and should be described in sufficient detail for others to assess the validity of outcomes. Hence, this study aimed to create a list of potential attributes and levels which can be used in a DCE study to elicit preferences for chronic liver disease screening programmes.

Key attributes were developed through a multi-stage, mixed methods design. Focus groups were held with consumers and health care providers on attributes of community screening programmes for liver disease. Stakeholders then prioritised attributes generated from the focus group in order of importance via an online prioritisation survey. The outcomes of the prioritisation exercise were then reviewed and refined by an expert panel to ensure clinically meaningful levels and relevance for a DCE survey.

Fifteen attributes were generated during the focus group sessions deemed necessary to design liver disease screening services. Outcomes of the prioritisation exercise and expert panel stages recognised five attributes, with three levels each, for inclusion in a DCE survey to elicit consumer preferences for community screening for liver disease. This study also highlights broader social issues such as the stigma around liver disease that require careful consideration by policy makers when designing or implementing a liver screening programme.

The attributes and levels identified will inform future DCE surveys to understand consumer preferences for community screening programmes for liver disease. In addition, the outcomes will help inform the implementation of the LOCATE-NAFLD programme in real-world practice, and could be relevant for other liver and non-liver related chronic disease screening programmes.

Metabolic-associated fatty liver disease (MAFLD) and diabetic kidney disease (DKD) share various pathophysiological factors, and epidemiological evidence suggests that these two diseases are associated. Albuminuria and the estimated glomerular filtration rate, which are conventional biomarkers of DKD, are reportedly associated with the risk or severity of MAFLD. Recently, novel DKD biomarkers reflecting renal tubular injury have been introduced to complement conventional DKD markers. In this article, we looked at previous studies that showed an association between MAFLD and DKD, and also reviewed the significance of DKD biomarkers as predictive risk factors for MAFLD.

The relationship between metabolic derangements and fatty liver development are undeniable, since more than 75% of patients with type 2 diabetes mellitus present with fatty liver. There is also significant epidemiological association between insulin resistance (IR) and metabolic (dysfunction)-associated fatty liver disease (MAFLD). For little more than 2 years, the nomenclature of fatty liver of non-alcoholic origin has been intended to change to MAFLD by multiple groups. While a myriad of reasons for which MAFLD is thought to be of metabolic origin could be exposed, the bottom line relies on the role of IR as an initiator and perpetuator of this disease. There is a reciprocal role in MAFLD development and IR as well as serum glucose concentrations, where increased circulating glucose and insulin result in increased de novo lipogenesis by sterol regulatory element-binding protein-1c induced lipogenic enzyme stimulation; therefore, increased endogenous production of triglycerides. The same effect is achieved through impaired suppression of adipose tissue (AT) lipolysis in insulin-resistant states, increasing fatty acid influx into the liver. The complementary reciprocal situation occurs when liver steatosis alters hepatokine secretion, modifying fatty acid metabolism as well as IR in a variety of tissues, including skeletal muscle, AT, and the liver. The aim of this review is to discuss the importance of IR and AT interactions in metabolic altered states as perhaps the most important factor in MAFLD pathogenesis.

Nonalcoholic fatty liver disease is a multisystem condition with effects beyond the liver. The identification of chronic kidney disease as an independent mediator of nonalcoholic fatty liver disease or associated entity with shared cardiometabolic risk factors remains controversial and continues to draw scientific interest. With increasing prevalence of nonalcoholic fatty liver disease and lack of Food and Drug Administration approved therapies, these shared cardiometabolic risk factors have drawn significant attention. In this article, we review shared pathophysiological mechanisms between nonalcoholic fatty liver disease and chronic kidney disease along with current treatment strategies that might be useful for both disease processes.

The effects of nonalcoholic fatty liver disease on the risk of end-stage renal disease (ESRD) remain unclear. We investigated the association between the fatty liver index (FLI) and risk of ESRD in patients with type 2 diabetes.

This population-based observational cohort study enrolled patients with diabetes who underwent health screening between 2009 and 2012 and utilized data from the Korean National Health Insurance Services. The FLI functioned as a surrogate marker for the presence of hepatic steatosis. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate < 60 ml/min/1.73 m² calculated using the Modification of Diet in Renal Disease equation. We performed Cox proportional hazards regression.

Incident ESRD developed in 19,476 of 1,900,598 patients with type 2 diabetes during a median follow-up of 7.2 years. After adjusting for conventional risk factors, patients with high FLI scores had a higher risk for ESRD: FLI, 30-59 [hazard ratio (HR) = 1.124; 95% confidence interval (CI), 1.083-1.166]; FLI ≥ 60 [HR = 1.278; 95% CI, 1.217-1.343] compared with those with FLI < 30. The association between a high FLI score (≥ 60) and incident ESRD was more prominent in women than in men (male, FLI ≥60: HR, 1.106; 95% CI = 1.041-1.176 and female, FLI ≥ 60: HR, 1.835; 95% CI = 1.689-1.995). The association between a high FLI score (≥ 60) and the risk of ESRD differed according to baseline kidney function. High FLI scores increased the risk of ESRD (HR = 1.268; 95% CI, 1.198-1.342) in patients with CKD at baseline.

High FLI scores are associated with a greater risk of ESRD in patients with type 2 diabetes with CKD at baseline. Close monitoring and appropriate management of hepatic steatosis may aid in preventing the progression of kidney dysfunction in patients with type 2 diabetes and CKD.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is an alternative description and classification of non-alcoholic fatty liver disease (NAFLD) that may have better utility than NAFLD in clinical practice. We performed a meta-analysis to quantify the magnitude of the association between MAFLD and risk of both prevalent and incident chronic kidney disease (CKD).

We systematically searched PubMed, Medline (OVID), Embase (OVID), Web of Science and Cochrane Library from database inception until 29 May 2022. We included observational studies examining the association between MAFLD and risk of CKD, defined by estimated glomerular filtration rate ≤60 mL/min/1.73 m2 or presence of abnormal albuminuria. Meta-analysis was performed using random-effects models to obtain summary HRs or ORs with 95% CIs.

Seventeen observational studies with aggregate data on 845 753 participants were included in meta-analysis. In the 7 cohort studies, the pooled random-effects HR for incident CKD in patients with MAFLD was 1.29 (95% CI 1.17 to 1.41, I2=87.0%). In the 10 cross-sectional studies, the pooled random-effects OR for prevalent CKD in patients with MAFLD was 1.35 (95% CI 1.11 to 1.64, I2=92.6%).

MAFLD is significantly associated with an increased prevalence and incidence of CKD.

CRD42022352366.

With the rising global prevalence of fatty liver disease related to metabolic dysfunction, the association of this common liver condition with chronic kidney disease (CKD) has become increasingly evident. In 2020, the more inclusive term metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to replace the term non-alcoholic fatty liver disease (NAFLD). The observed association between MAFLD and CKD and our understanding that CKD can be a consequence of underlying metabolic dysfunction support the notion that individuals with MAFLD are at higher risk of having and developing CKD compared with those without MAFLD. However, to date, there is no appropriate guidance on CKD in individuals with MAFLD. Furthermore, there has been little attention paid to the link between MAFLD and CKD in the Nephrology community.

Using a Delphi-based approach, a multidisciplinary panel of 50 international experts from 26 countries reached a consensus on some of the open research questions regarding the link between MAFLD and CKD.

This Delphi-based consensus statement provided guidance on the epidemiology, mechanisms, management and treatment of MAFLD and CKD, as well as the relationship between the severity of MAFLD and risk of CKD, which establish a framework for the early prevention and management of these two common and interconnected diseases.