Lactucin and lactucopicrin are the characteristic lipid-lowering active components found in Cichorium glandulosum. However, their effects and underlying mechanisms in obesity remain unclear. In the present study, C57BL/6J mice were simultaneously subjected to a high-fat diet (HFD) and treated with drugs to investigate the impacts of lactucin and lactucopicrin on HFD-induced obese mice. The results demonstrated that in HFD obese mice, lactucin and lactucopicrin significantly decreased body weight and the weights of adipose tissues, improved serum metabolic parameters, and increased the content of irisin. Regarding the intermediate metabolites of intestinal flora, which are closely associated with white adipose tissue (WAT) browning, lactucin and lactucopicrin treatment led to a reduction in the levels of 12-α-OH/non-12-α-OH bile acids (BAs) and also tended to enhance the levels of short-chain fatty acids (SCFAs). qRT-PCR results indicated that lactucin and lactucopicrin treatment elevated the expression levels of genes related to beige fat markers, thermogenesis, mitochondrial biogenesis, and lipolysis in WAT, as well as those of thermogenesis and lipolysis genes in brown adipose tissue (BAT). Western blot analysis revealed that lactucin and lactucopicrin up-regulated the expression of uncoupling protein 1 (UCP1), the core protein in thermogenesis, in both WAT and BAT. Moreover, they also up-regulated the expression levels of AMP-activated kinase (AMPK), sirtuin 1 (SIRT1), and PPARγ coactivator 1-alpha (PGC-1α), which are key pathway proteins involved in WAT browning. Furthermore, 16S rRNA sequencing results showed that in HFD obese mice, lactucin and lactucopicrin improved the composition and function of the intestinal microbiota. In conclusion, lactucin and lactucopicrin may promote WAT browning by activating the AMPK/SIRT1/PGC-1α pathway, thereby ameliorating obesity in HFD mice.

We assessed the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and significant liver fibrosis in adults with type 1 diabetes mellitus (T1DM) and the association of MASLD with insulin sensitivity and continuous glucose monitoring metrics.

We consecutively enrolled 198 adults with T1DM undergoing vibration-controlled transient elastography with liver stiffness measurement (LSM) and controlled attenuation parameter (CAP). All participants had a continuous glucose monitoring (CGM) device. Insulin sensitivity was evaluated by estimated glucose disposal rate (eGDR). MASLD was defined as CAP ≥ 248 db/m and the presence of at least one cardiometabolic risk factor. Significant liver fibrosis was defined as LSM ≥ 7 kPa.

Patients had a mean age of 56 years, mean BMI of 26.0 ± 5.9 kg/m2, and mean eGDR of 7.1 ± 2.3 mg/kg/min. 73 (37%) patients had MASLD (using a CAP threshold of 274 dB/m), 16 (8.1%) of whom had significant liver fibrosis. MASLD was associated with a significantly lower eGDR (beta coefficient = -0.367, 95% confidence interval -0.472 to -0.261; p < 0.001). This association remained significant, even after adjustment for age, sex, body mass index, plasma triglycerides, diabetes duration, daily insulin dose, time above the range of glucose levels, LSM and chronic kidney disease. No association was observed between MASLD and CGM-derived metrics. These results were not different when we used a CAP threshold of 274 dB/m for diagnosing MASLD.

In T1DM, MASLD was inversely associated with eGDR and biomarkers of insulin resistance but not with CGM-derived metrics.

Non-alcoholic fatty liver disease (NAFLD) is strongly associated with dyslipidemia, and the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) is a more comprehensive indicator of lipids. This study aimed to investigate the association between NHHR and hepatic steatosis and liver fibrosis. The 2017-2020 national health and nutrition examination survey (NHANES) dataset was used for the cross-sectional survey. NHHR was calculated by lipid profiling, and the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) were determined by vibration-controlled transient elastography (VCTE). Multiple linear regression models were used to test the linear association between NHHR and hepatic steatosis and liver fibrosis. Fitted smoothing curves and threshold effect analysis were used to describe the nonlinear relationships. This population-based study included 6575 adults (≥ 18 years). After adjusting for covariates, we found a U-shaped association between NHHR and hepatic steatosis, with a breakpoint of 1.26. There was a negative association on the left side of the breakpoint (OR [95% CI] - 24.31 [- 43.92, - 4.70]) and a positive association on the right side of the breakpoint (OR [95% CI] 3.82 [2.05, 5.59]). There was no significant association between NHHR and liver fibrosis. In addition, subgroup analyses and interaction tests showed stable results. In summary, NHHR has a U-shaped association with hepatic steatosis and no significant association with liver fibrosis. Keeping NHHR below 1.26 may be an effective option to reduce the risk of hepatic steatosis. NHHR is a more efficient and cost-effective marker for NAFLD surveillance that can be utilized in future clinical practice.

Lifestyle-induced weight reduction remains crucial for managing type 2 diabetes and steatotic liver disease, but its effectiveness varies. We postulated that the G allele in the rs738409 single nucleotide polymorphism within patatin-like phospholipase domain-containing protein 3 (PNPLA3), which associates with metabolic dysfunction-associated steatotic liver disease, also modulates diet-related metabolic effects.

Participants with type 2 diabetes were randomized to 8-week hypocaloric diets (energy intake: -1,256 kJ/d of, <30 kcal% fat): high in cereal fiber and coffee excluding red meat (HF-RM + C; n = 16), or low in cereal fiber, devoid of coffee, but high in red meat (LF + RM-C; n = 15). Whole-body insulin sensitivity (M value) was assessed using [2H]glucose and hyperinsulinemic-normoglycemic clamps, hepatic lipid content (HCL) and body fat volumes by magnetic resonance spectroscopy/imaging before and after intervention.

Despite comparable weight loss, HCL decreased more in non-carriers (-65 %) than in G-allele carriers (-36 %) upon HF-RM + C diet (both p < 0.05 vs baseline and between groups), but only among non-carriers (-46 %, p < 0.05 vs baseline) upon LF + RM-C. Upon HF-RM + C diet, increase in insulin sensitivity was not different between carriers (+27 % p = 0.051 from baseline) and non-carriers (+21 %, p = 0.032 from baseline), p > 0.05 for between-group comparison. Upon LF + RM-C diet, both groups equally improved their whole-body insulin sensitivity (+42 % for non-carriers and +37 % for carriers, p < 0.05 vs baseline). Upon HF-RM + C diet, non-carriers decreased circulating interleukin-18 from baseline by -31 %, whereas, upon LF + RM-C diet, non-carriers decreased circulating anti-inflammatory interleukin-1 receptor antagonist levels by 14 % (both p < 0.05 vs baseline).

Humans with the PNPLA3 G-allele show modified dietary-induced effects on steatotic liver disease in type 2 diabetes despite body weight reduction. Registration at Clinicaltrials.gov, Identifier number: NCT01409330.

Complications of diabetes mellitus have significant impacts on morbidity, mortality, quality of life, and health costs for individuals. Setting and achieving glycemic targets to prevent these complications is a top priority when managing diabetes. However, patients often already have complications when diagnosed with diabetes mellitus. Therefore, methods to prevent disease progression become a crucial component of diabetes management. The purpose of this article is to review glycemic targets and methods of screening and managing diabetes-related complications.

A PubMed review of the literature pertaining to diabetes mellitus, glycemic targets, microvascular complications, and macrovascular complications was conducted. We reviewed articles published between 1993 and 2024. Guidelines published by nationally recognized organizations in the fields of diabetes, nephrology, and cardiology were referenced. Public health statistics obtained by the Center for Disease Control and Prevention and the National Kidney Foundation were used.

Achieving glycemic targets and screening for diabetes-related complications at appropriate intervals remains the key factor for early detection and intervention. An algorithmic approach to glycemic management based on individual risk factors is beneficial in choosing pharmacotherapy.

The consequences of diabetes-related complications can be detrimental. However, achieving and maintaining glycemic targets combined with diligent screening, reduction of risk factors, and prompt treatment can halt disease progression.

The continuum of metabolic syndrome encompasses a spectrum of dysfunctions impacting obesity-linked insulin resistance, glucose homeostasis, lipid metabolism and pro-inflammatory immune responses. The global prevalence of metabolic diseases, including diabetes, chronic liver disease, cardiometabolic disease and kidney disease, has surged in recent decades, contributing significantly to population mortality. Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, is a leading cause of liver disease worldwide. MASLD poses a significant global health challenge with its rising prevalence, placing a substantial burden on healthcare systems, impacts patient well-being and incurs significant economic costs. Addressing MASLD requires a comprehensive understanding of its interconnected factors, including its prevalence, healthcare burden and economic implications. Lack of awareness, imprecise non-invasive diagnostic methods and ineffective preventive interventions are core components of the MASLD-related problem.

The aim of this article was to summarise the global burden of MASLD from the payer's perspective.

We carried out a review of the global comprehensive burden of MASLD. These topics led to discussions and insights by an expert panel during the 7th Metabolic Continuum Roundtable meeting, which took place in November 2023. This meeting focused on the burden, patient-reported outcomes and health economics, from payor and societal perspectives, and aimed to identify opportunities for improving patient care, optimise resource allocation and mitigate the overall impact on individuals and society related to MASLD. During the roundtable, an emphasis emerged on the need for greater awareness and strategic deployment of diagnostic, therapeutic and preventative measures to address MASLD effectively.

The global burden of MASLD is high and growing. Prioritising the prevention of metabolic dysregulation and timely therapeutic interventions can yield a holistic strategy to combat MASLD, its progression and potentially lower disease costs.

NCT06309992.

To investigate the prevalence of liver fibrosis, and the association between caffeine intake and fibrosis in populations with different glucose metabolism status.

This was a cross-sectional study based on the National Health and Nutrition Examination Survey (2005-March 2020). Of the 39,221 adult individuals with no necessary laboratory results missing, a total of 23,711 eligible individuals were included in the study. Individuals were divided into T2DM, prediabetes, and diabetes-free groups. Fibrosis-4 index was calculated to evaluate the risk of liver fibrosis. Caffeine intake was obtained through a 24-hour dietary recall.

The mean ± SE age of prediabetes group was 53 ± 0·4 years, and in type 2 diabetes mellitus group, the individuals have a mean ± SE age of 62 ± 0·3 years. The participants with type 2 diabetes mellitus had significantly higher risk of liver fibrosis than those with prediabetes or normal glucose tolerance (5·9% vs. 3·2% vs. 2·5%, P < 0·001). Compared to individuals with daily caffeine intake < 78 mg, individuals with daily caffeine intake ≥ 78 mg had significantly lower risk of liver fibrosis in all subgroups (odds ratio: diabetes-free group: 0·698[0·577-0·846]; prediabetes group: 0·553[0·397-0·769]; type 2 diabetes mellitus group: 0·720[0·556-0·933]; all P < 0·05).

Prevalence of liver fibrosis is high in patients with type 2 diabetes mellitus and prediabetes. It is indicated that individuals with prediabetes should also be screened for fibrosis. Caffeine intake ≥ 78 mg per day is associated with a lower risk of liver fibrosis.

International guidelines suggest screening for advanced fibrosis due to metabolic dysfunction-associated steatotic liver disease in people with type 2 diabetes, but how to implement these guidelines in clinical care remains unclear. We hypothesise that examination with VCTE could be implemented simultaneously with retina scanning with a high acceptance rate in people with type 2 diabetes.

In this cross-sectional study, we offered VCTE to people with type 2 diabetes referred to routine retina scanning in a large retina scanning facility in Stockholm, Sweden. We excluded people with type 1 diabetes, currently pregnant, with known liver disease, reporting high alcohol consumption, who did not speak Swedish, or younger than 18 years. Between Nov 6, 2020, and June 20, 2023, we conducted surveys with included participants and collected data from medical records on diabetes retinopathy, sex, and VCTE measurements. Increased liver stiffness was defined as at least 8·0 kPa, and possible advanced fibrosis as more than 12·0 kPa. Presence of metabolic dysfunction-associated steatotic liver disease was defined as a controlled attenuation parameter (CAP) value of 280 dB/m or higher. Participants with a liver stiffness measurement of at least 8·0 kPa or those with unreliable measurements were subsequently referred for a secondary evaluation at a liver specialist, including a follow-up liver stiffness measurement with VCTE. The primary outcome was the proportion of eligible people approached for screening who accepted. Secondary outcomes were the prevalence of elevated liver stiffness (≥8·0 kPa or >12·0 kPa), presence of metabolic dysfunction-associated steatotic liver disease, and the proportion of elevated liver stiffness readings at the first VCTE examination that were not elevated in the secondary evaluation with a liver specialist. Secondary outcomes were assessed in all participants who accepted screening, except false positives, which were assessed only in participants who had a second examination.

1301 participants were eligible to undergo assessment with VCTE, which was accepted by 1005 (77·2%). 973 (96·8%) participants had complete measurements, of whom 504 (51·8%) had CAP values of 280 dB/m or higher, indicating metabolic dysfunction-associated steatotic liver disease. Of 977 participants with reliable liver stiffness measurements, 154 (15·8%) had values of at least 8·0 kPa, suggestive of liver fibrosis, and 49 (5·0%) had values higher than 12·0 kPa, indicating possible advanced fibrosis. However, upon reassessment with a second VCTE after referral, 56 (45·2%) of 124 individuals had values less than 8·0 kPa. 74 (7·4%) of 1005 participants had a final liver stiffness of at least 8·0 kPa; 29 (2·9%) had values greater than 12·0 kPa.

Simultaneous examination with VCTE alongside retina scanning had a high acceptance rate among people with type 2 diabetes and could be a strategy for case-finding of people with fibrosis due to metabolic dysfunction-associated steatotic liver disease. However, a high proportion of participants in our study with elevated liver stiffness measurement at the screening visit did not have an elevated liver stiffness measurement at secondary evaluation, suggesting false-positive findings were common.

Gilead Sciences, Pfizer, Region Stockholm, Åke Wiberg Foundation, and Bengt Ihre Foundation.

Metabolic dysfunction-associated steatohepatitis (MASH), the progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD), is linked to cardiometabolic risk factors such as obesity and type 2 diabetes (T2D). The rising prevalence of MASH and risk of hepatic and extra-hepatic complications emphasize the need for a better understanding of disease progression and associated outcomes. This study aimed to evaluate the incidence of, and demographic and clinical characteristics associated with, progression to MASH-related complications by disease severity in patients with non-cirrhotic MASH or MASH cirrhosis. Alignment between noninvasive tests (NITs) and biopsy-determined fibrosis stage was also assessed.

This analysis used data from the TARGET-NASH cohort that includes adults with MASH across academic and community sites in the United States. Patients with non-cirrhotic MASH or MASH cirrhosis were stratified by disease severity based on fibrosis stage or cirrhosis. Progression to MASH-related outcomes, including all-cause mortality, cirrhosis, and liver transplantation, was assessed.

Among the 2378 patients included in this analysis, 48% had MASH cirrhosis. Incidence of all-cause mortality increased with disease severity from 0.14/100 person-months (100PM) at fibrosis stage 0-1 (F0-F1) to 2.02/100PM with compensated cirrhosis and 4.62/100PM with decompensated cirrhosis. Compared with patients with F0-F1, risk of progression to cirrhosis was higher in patients with F3 [hazard ratio (HR), 95% confidence interval (CI); 18.66, 10.97-31.73] and F2 (HR, 95% CI; 3.74, 2.00-6.98). Among those who progressed to MASH-related outcomes, 67.9% had T2D and 73.9% had hypertension. Vibration-controlled transient elastography showed better alignment with biopsy-determined fibrosis stage than Fibrosis-4 Index (FIB-4).

Progression to all-cause mortality in patients with MASH was significantly associated with the presence of higher fibrosis stage and cirrhosis. Cardiometabolic comorbidities such as T2D and hypertension were prevalent in patients with MASH progression. Early identification and management of MASH may mitigate disease progression and liver-related complications.

Chronic liver diseases (CLD) are a leading cause of death worldwide, with alcohol consumption and metabolic risk factors as the two reasons accounting for the majority of cases of CLD in many developed countries. Currently there is a lack of specific strategies for early diagnosis of CLD and consequently most cases are diagnosed in advanced stages of the disease, which is associated with negative consequences for disease management and prognosis. Screening for CLD is based on either detection of chronic viral hepatitis B and C, or detection of liver fibrosis in patients with steatotic liver disease related to alcohol or metabolic dysfunction. There are non-invasive tools available for detection of liver fibrosis, including serological and imaging-based tests. Clinical practice guidelines recommend screening for liver fibrosis using algorithms that combine different non-invasive tests, with widely available but low accuracy tests such as FIB-4 for a first screening step in primary care setting, and other tests with less availability but higher accuracy, such as Transient Elastography or Enhanced Liver Fibrosis Test as a second step. There are different pathways for early detection of patients with CLD from primary to specialized care, where primary care providers are key for early detection, management and referral of patients. In addition, intervention on metabolic risk factors and alcohol consumption should be carried out in collaboration between specialized therapy and primary care. This review describes liver fibrosis from the community perspective, highlighting gaps in knowledge on how to define the optimal combination of tests, target population, the ideal pathway of care for CLD, and how to increase implementation of programs for early diagnosis of liver diseases in clinical practice.

The aim of this study was to determine the prevalence of advanced hepatic fibrosis and to individualize using Bayesian analysis its associated risk factors in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) being cared for in three Alsatian cardio-metabolic health networks in the North East of France. Overall, 712 patients aged ≥18 years with a female predominance were included into a prospective, cross-sectional, and observational study. Advanced fibrosis and severe steatosis were evaluated using transient elastography (FibroScan®). The proportion of MASLD patients was 80% and 84% in women and men (difference -4.2% [-10.0; 1.9]), respectively. Advanced fibrosis was observed in 11% of patients, being more common in men (16.9%) than women (7.5%) (difference 9.4 [4.3-15.0]). Severe steatosis was also more common in men (74.9%) than women (63.4%) (difference 11.4 [4.2-18.2]). Only three of the tested variables were likely associated with advanced fibrosis: gender (OR: 1.78 [1.17-2.68]; Pr [OR >1] = 1), T2DM (OR: 1.54 [1-2.37]; Pr [OR >1] = 0.97) and hypertriglyceridemia (OR: 1.49 [0.97-2.27]; Pr (OR >1) = 0.97). In conclusion, this study confirmed the usefulness of assessing hepatic fibrosis in patients with metabolic dysfunction. Therefore, access to FibroScan® should be facilitated in all cardio-metabolic health networks.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common condition leading to chronic liver disease which generates substantial healthcare costs. Our aim was to model the impact of a hypothetical pharmacologic therapy which halts MASLD fibrosis progression on disease and economic burden.

The US MASLD disease burden model is a Markov model which forecasts disease progression and the impact of diagnosis and treatment. Diagnostic costs for all patients and direct costs for patients with MASLD-related liver disease were also incorporated. MASLD disease burden and economic impacts were modeled for five scenarios: a no treatment case and four interventions incorporating the impact of gradually increasing awareness, screening, and diagnosis, and treatment with anti-steatotic therapy and a future, hypothetical therapy that halts fibrosis progression.

Treatment with therapy which only reverses steatosis had minimal (<1 to 2%) effect on cumulative chronic liver disease cases and healthcare costs averted. The scenarios in which a hypothetical therapy halts fibrosis progression resulted in reductions in cases of decompensated cirrhosis (11-39%), hepatocellular carcinoma (10-34%), and liver-related deaths (8-31%), a 9-31% reduction in cumulative DALYs, and $40.5 to $99.1B incremental healthcare costs averted.

Increasing diagnosis and treatment for the MASLD population with moderate-to-advanced fibrosis will prevent advanced liver disease and death and will result in reducing the associated direct healthcare costs. Increasing awareness, screening and diagnosis along with introducing pharmacologic therapies that halt fibrosis progression are necessary to realize health and economic benefits for the MASLD population.

Metabolic dysfunction-associated steatotic liver disease (MASLD), the most rapidly increasing and prevalent cause of chronic liver disease, is associated with substantial healthcare costs. As disease burden and costs mount, pharmacologic therapy which halts MASLD fibrosis progression is coming to fruition. Modeling the impact on disease progression of a hypothetical pharmacologic therapy which halts MASLD fibrosis progression through multiple scenarios provides insights into the key drivers of the disease and costs associated with it. This should help to facilitate best policies and practices to mitigate the burden of MASLD.

To estimate the prevalence and associated factors of hepatic steatosis and fibrosis in adults with type 2 diabetes (T2DM) in the United States.Data were retrieved from the 2017‒March 2020 prepandemic cycle of the National Health and Nutritional Examination and Survey (NHANES). The study population included patients with T2DM. The controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) were used to assess hepatic steatosis and fibrosis, respectively. A total of 1,290 T2DM patients were included, 85.2% (1044 patients) of whom presented with hepatic steatosis (CAP>248 dB/m). Among the 1044 T2DM patients with metabolically associated fatty liver disease (MAFLD), 29.5% developed hepatic fibrosis (LSM>8 kPa). Non-Hispanic black individuals (adjusted OR = 0.4008), BMI (adjusted OR = 1.1627), HbA1c (adjusted OR = 1.1450), TG (adjusted OR = 1.2347), HDL (adjusted OR = 0.4981), ALT (adjusted OR = 1.0227), AST (adjusted OR = 0.9396), and albumin (adjusted OR = 1.7030) were independently associated with steatosis. Age (adjusted OR = 1.0300), female sex (adjusted OR = 0.6655), BMI (adjusted OR = 1.1324), AST (adjusted OR = 1.0483), and GGT (adjusted OR = 1.0101) were independently associated with fibrosis. Heart failure was an independent factor associated with advanced fibrosis (adjusted OR = 1.9129) and cirrhosis (adjusted OR = 2.228). In the United States, hepatic steatosis is highly prevalent among T2DM patients, with 29.5% of these patients developing hepatic fibrosis. Some components of metabolic syndrome are related to hepatic steatosis and fibrosis. Moreover, heart failure is an independent factor associated with advanced fibrosis and cirrhosis.

Steatotic liver disease (SLD) is a significant public health burden. Previously, we estimated prepandemic SLD prevalence determined by transient elastography-assessed hepatic steatosis and fibrosis in the United States. We now estimate the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and examine associations with lifestyle, socioeconomic, and other factors.

Liver stiffness and controlled attenuation parameters were assessed on 13,538 non-Hispanic White, non-Hispanic Black, non-Hispanic Asian, and Hispanic men and women aged 20 years and over in the National Health and Nutrition Examination Survey 2017 to March 2020 and August 2021 to August 2023. The prevalence of SLD (controlled attenuation parameter >300 dB/m) was 28.7%, fibrosis (liver stiffness >8 kPa) was 11.3%, and MASLD was 25.6%. Between the 2 survey cycles, the age-standardized SLD prevalence was not significantly different, MASLD prevalence decreased (26.8%-23.6%), and fibrosis prevalence increased (10.4%-12.7%). In multivariable-adjusted analysis, both MASLD and fibrosis were associated with diabetes, higher body mass index, higher waist-to-hip ratio, elevated blood pressure, and inversely associated with non-Hispanic Black race-ethnicity. MASLD was also associated with male sex, non-Hispanic Asian race-ethnicity, prediabetes, higher total cholesterol, lower HDL cholesterol, and greater sedentary lifestyle. Fibrosis was also associated with SLD, lower total cholesterol, and less education.

In the US population, MASLD and fibrosis prevalence are high along with obesity and diabetes. Our findings suggest that early detection of chronic liver disease and targeting lifestyle and other modifiable risk factors may slow disease progression toward advanced fibrosis and cirrhosis.

Insufficient nocturnal sleep was associated with a higher risk of fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Dietary fiber intake may improve the stimulate the secretion of sleep cytokines, inhibit the inflammatory pathway, contribute to regulating sleep disorders and alleviate liver fibrosis. The associations of dietary fiber intake, sleep patterns, with liver fibrosis remain unclear. The study aimed to explore the associations between dietary fiber, sleep, and liver fibrosis, as well as the moderating effect of dietary fiber intake between sleep patterns and liver fibrosis in MASLD patients.

Using data from the National Health and Nutrition Examination Survey (NHANES) database spanning from 2017 to 2020, a cross-sectional study included participants with MASLD was performed to assess the relationship between sleep patterns, dietary fiber intake, and liver fibrosis. Weighted univariate and multivariate logistic regression models were used to examine the linear connection between sleep pattern, dietary fiber intake, and liver fibrosis. Restricted cubic spline (RCS) method was also performed to describe the nonlinear relationship. A two-part linear regression model was also used to estimate threshold effects. The moderating effect of dietary fiber intake was further investigated in different subgroups. All results were presented as odds ratios (ORs) and 95% confidence intervals (CIs).

Totally, 1343 MASLD patients were included for final analysis. Among them, 207 (15.41%) have liver fibrosis. Dietary fiber intake did not correlate significantly with sleep pattern in patients with MASLD (Spearman's r = -0.028, P = 0.1678). Poor sleep pattern was related to higher odds of liver fibrosis (OR = 3.23, 95%CI: 1.05-9.90), while dietary fiber intake ≥ 15 gm/day was associated with lower liver fibrosis risk (OR = 0.51, 95%CI: 0.32-0.83). On the association between sleep pattern and liver fibrosis stratified by dietary fiber intake revealed that poor sleep patterns (OR = 15.13, 95%CI: 4.40-52.01) remained associated with increased liver fibrosis risk among individuals with dietary fiber intake < 15 gm/day. No connection was observed between poor sleep patterns and liver fibrosis in MASLD patients with higher dietary fiber intake, with moderate dietary fiber supplementation beneficial in mitigating poor sleep patterns associated with liver fibrosis. The similar findings were also found in patients aged < 50 years old, ≥ 50 years old, females, those with and without CVD groups, hypertension, and dyslipidemia. Particularly, dietary fiber intake also moderates the relationship between sleep patterns and liver fibrosis in the F4 stage (OR = 13.26, 95%CI: 4.08-43.11).

Dietary fiber intake affects the relationship between sleep patterns and liver fibrosis in MASLD patients.

To describe the prevalence, clinical characteristics and risk factors of liver steatosis and fibrosis in type 2 diabetes mellitus (T2DM) patients in eastern China.

A cross-sectional, multicentre study based on an ongoing cohort study.

16 clinics in eastern China, including primary clinics to tertiary hospitals.

1816 patients with T2DM diagnosis who met the inclusion criteria were recruited into the study.

Participants underwent elastography examination.

Descriptive analysis was performed to calculate the prevalence and characteristics of liver steatosis and fibrosis. The correlated factors were analysed using single- and multivariate logistic regression analysis.

The prevalence of liver steatosis in T2DM patients is 69.7%, with 46% moderate to severe steatosis. 34.6% and 6.7% of the patients were detected with liver fibrosis and cirrhosis. Steatosis patients were younger, had higher body mass index (BMI), higher levels of insulin resistance and more severe lipid metabolism disorders. Similar trends of differences were observed in patients with fibrosis. Female gender (OR=0.574, 95% CI 0.381 to 0.865), BMI (OR=1.491, 95% CI 1.375 to 1.616), disease duration, inflammation and serum lipid profile markers were risk factors of steatosis, while BMI (OR=1.204, 95% CI 1.137 to 1.275) and female gender (OR=0.672, 95% CI 0.470 to 0.961) were still the most significant predictors of liver fibrosis.

The prevalence of liver steatosis and fibrosis were high in patients with T2DM. Liver steatosis and fibrosis in these patients appeared to be more associated with lipid metabolism disorders and insulin resistance rather than glucose levels.

Clinical trial: NCT05597709.

Glucose metabolism status (GMS) is linked to non-alcoholic fatty liver disease (NAFLD). Higher levels of advanced glycation end products (AGEs) are observed in people with type 2 diabetes mellitus (T2DM) and NAFLD. We examined the association between GMS, non-invasive tests and AGEs, with liver steatosis and fibrosis.

Data from The Maastricht Study, a population-based cohort, were analysed. Participants with alcohol overconsumption or missing data were excluded. GMS was determined via an oral glucose tolerance test. AGEs, measured by skin autofluorescence (SAF), were assessed using an AGE Reader. Associations of GMS and SAF with the fibrosis-4 score (FIB-4), Forns index (FI) and fatty liver index (FLI) were investigated using multivariable linear regression, adjusted for sociodemographic, lifestyle and clinical variables.

1955 participants (56.6%) were analysed: 598 (30.6%) had T2DM, 264 (13.5%) had pre-diabetes and 1069 (54.7%) had normal glucose metabolism. Pre-diabetes was significantly associated with FLI (standardised regression coefficient (Stβ) 0.396, 95% CI 0.323 to 0.471) and FI (Stβ 0.145, 95% CI 0.059 to 0.232) but not FIB-4. T2DM was significantly associated with FLI (Stβ 0.623, 95% CI 0.552 to 0.694) and FI (Stβ 0.307, 95% CI 0.226 to 0.388) but not FIB-4. SAF was significantly associated with FLI (Stβ 0.083, 95% CI 0.036 to 0.129), FI (Stβ 0.106, 95% CI 0.069 to 0.143) and FIB-4 (Stβ 0.087, 95% CI 0.037 to 0.137).

The study showed that adverse GMS and higher glycaemia are positively associated with steatosis. FI, but not FIB-4, was related to adverse GMS concerning fibrosis. This study is the first to demonstrate that SAF is positively associated with steatosis and fibrosis.

In this cross-sectional study including patients with type 2 diabetes mellitus (T2DM) we aimed to explore the relationship between serum 25-hydroxy vitamin (25(OH)D) level and liver steatosis and fibrosis in the Chinese population.

Patients visiting 16 clinical centers with T2DM were recruited. Their liver steatosis and fibrosis status were then assessed using elastography. Factors associated with steatosis and fibrosis were explored using regression analysis. Correlations between serum 25(OH)D levels and other patient characteristics were analyzed using linear regression.

In total, 1,513 patients with T2DM were included in the study. The prevalence of steatosis and fibrosis was 69.7%, and 34.6%, separately. A lower level of 25(OH)D was detected in patients with liver steatosis compared to those without, although it was not an independent predictor of this condition. However, 25(OH)D level was independently associated with liver fibrosis even when adjusted for age, sex, body mass index, hemoglobin A1c, insulin, and homeostatic model assessment of insulin resistance (OR = 0.964 [0.935-0.993], P = 0.015). When patients were separated into subgroups by sex, a correlation between 25(OH)D and fibrosis was identified in the male group (OR = 0.969 [0.940-0.998], P = 0.038).

In conclusion, this multi-center, cross-sectional study in patients with T2DM showed that serum 25-hydroxy vitamin D level was strongly associated with liver fibrosis and this relationship was more pronounced in male patients.

https://clinicaltrials.gov/ct2/show/, identifier NCT05597709.

Provide a concise update on metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), as well as a practical approach to screening and initial evaluation.

Nomenclature changes have placed a greater focus on cardiometabolic risk factors in the definition of MASLD. Screening for MASLD is by stepwise noninvasive serum and imaging tests which can identify patients at risk for advanced fibrosis and liver-related complications. MASLD has been increasing in prevalence and disease burden but is underrecognized in primary care and endocrinology clinics. Multiple society guidelines, synthesized here, provide a framework for the initial approach in the diagnosis and evaluation of MASLD. Recent advances in pharmacologic treatment underline the importance of screening for patients who are at risk for advanced fibrosis as they are most likely to benefit from new drug classes, such as the liver-directed thyroid receptor agonist resmiterom.

Non-alcoholic (now: metabolic) steatohepatitis (MASH) is the progressive inflammatory form of metabolic dysfunction-associated steatotic liver disease (MASLD), which often coexists and mutually interacts with type 2 diabetes (T2D), resulting in worse hepatic and cardiovascular outcomes. Understanding the intricate mechanisms of diabetes-related MASH progression is crucial for effective therapeutic strategies. This review delineates the multifaceted pathways involved in this interplay and explores potential therapeutic implications. The synergy between adipose tissue, gut microbiota, and hepatic alterations plays a pivotal role in disease progression. Adipose tissue dysfunction, particularly in the visceral depot, coupled with dysbiosis in the gut microbiota, exacerbates hepatic injury and insulin resistance. Hepatic lipid accumulation, oxidative stress, and endoplasmic reticulum stress further potentiate inflammation and fibrosis, contributing to disease severity. Dietary modification with weight reduction and exercise prove crucial in managing T2D-related MASH. Additionally, various well-known but also novel anti-hyperglycemic medications exhibit potential in reducing liver lipid content and, in some cases, improving MASH histology. Therapies targeting incretin receptors show promise in managing T2D-related MASH, while thyroid hormone receptor-β agonism has proven effective as a treatment of MASH and fibrosis.

Liver fibrosis is associated with increased cardiovascular disease (CVD) risk and mortality. However, it is unknown how these risks compare in those with pre-diabetes (pre-DM) or diabetes (DM). We examined the association of FIB-4 levels, an indicator of liver fibrosis, with CVD risk and mortality according to DM status.

Prospective, longitudinal cohort study.

We examined 13,326 U.S. adults (6.7 % with DM) with FIB-4 measures classified as low (<1.30), intermediate (1.30- < 2.67), high (2.67- < 3.25), and very high (≥3.25). National Death Index linkage provided mortality status for CVD, liver-related, and all causes over 17.5 years.

We calculated 10-year ASCVD risk in persons without known ASCVD. Cox regression examined the relation of FIB-4 with mortality by DM status.

High/very high FIB-4 levels were greater in those with (2.2 %) vs. without (0.4 %) DM (p < 0.0001). Higher FIB-4 scores and DM were associated with greater estimated ASCVD risks (p < 0.0001); 44.5 % of those at high /very high FIB-4 levels had ≥20 % estimated ASCVD risk. CVD mortality hazard ratios (HRs) (95 % CI) associated with high/very high FIB-4 in those with pre-DM and DM were 8.76 (3.66-20.95), and 0.89 (0.22-3.53), respectively, and for total mortality were 5.46 (3.16-9.43), and 2.07 (0.90-4.74), respectively, which were attenuated after adjustment.

Our findings indicate the need for increased efforts to identify those at risk of liver fibrosis in adults with pre-DM or DM to prevent CVD and total mortality.

Patients with diabetes are at increased risk of dying from liver-related events, but little is known on whether this increased risk has changed in recent years.

The aim of the present study is to describe time trends in cause-specific liver-related mortality in people with and without diabetes from the general Italian population.

Data were retrieved from the health care utilization databases of Lombardy, a region of Italy that accounts for about 16% (almost 10 million) of its population. Annual cause-specific mortality rates and proportionate mortality were computed among individuals with and without diabetes from 2010 to 2019. Liver-related deaths were categorized as viral, alcohol related, and nonviral nonalcohol related (NVNA).

Liver diseases were responsible for 2% and 1% of deaths in people with and without diabetes (2019). Among patients with diabetes, the crude mortality rate for liver diseases decreased from 1.13 to 0.64 deaths per 1000 person-years from 2010 to 2019. The largest proportion of liver-related deaths was attributable to NVNA diseases and it increased from 63% in 2010 to 68% in 2019, with a corresponding relative reduction of viral causes (from 27% to 23%). The standardized mortality ratio for patients with diabetes was 3.35 (95% CI 2.96-3.76) for NVNA, 1.66 (95% CI 1.33-2.01) for viral hepatitis, and 1.61 (95% CI 1.13-2.17) for alcoholic liver disease and it remained relatively stable over time. Excess mortality risk in patients with diabetes for liver-related mortality was higher than for cardiovascular mortality and cancer.

While liver-related mortality rates decreased significantly among patients with diabetes, NVNA causes made up the majority of cases. Excess mortality for liver-related causes in patients with diabetes compared with controls remained constant in the studied period.

Metabolic-associated fatty liver disease (MAFLD) is the predominant form of chronic liver disease worldwide. This study was designed to investigate the proportion and characteristics of MAFLD within the general Chinese population and to identify the contributory risk factors for liver fibrosis among MAFLD individuals.

The participants were recruited from a cohort undergoing routine health evaluations at the Third Hospital of Hebei Medical University between May 2019 and March 2023. The diagnosis of MAFLD was based on the established clinical practice guidelines. The fibrosis-4 index score (FIB-4) was employed to evaluate hepatic fibrosis, with a FIB-4 score of ≥1.3 indicating significant fibrosis. Binary logistic regression analyses were used to determine risk factors associated with significant hepatic fibrosis in MAFLD.

A total of 22,970 participants who underwent comprehensive medical examinations were included in the analysis. The overall proportion of MAFLD was 28.77% (6608/22,970), with 16.87% (1115/6608) of these patients showing significant fibrosis as assessed using FIB-4. Independent risk factors for significant liver fibrosis in MAFLD patients were male (odds ratio [OR] = 0.676, 95% confidence interval [CI]: 0.558-0.821), hepatitis B surface antigen (HBsAg) positivity (OR = 2.611, 95% CI: 1.557-4.379), body mass index ≥23.00 kg/m2 (OR = 0.632, 95% CI: 0.470-0.851), blood pressure ≥130/85 mmHg (OR = 1.885, 95% CI: 1.564-2.272), and plasma glucose ≥5.6 mmol/L (OR = 1.815, 95% CI: 1.507-2.186) (all P <0.001).

The proportion of MAFLD in an urban Chinese population is 28.77%. About 16.87% of MAFLD patients presented with significant liver fibrosis.

Multiple modifications of metabolic syndrome diagnostic criteria have been made-NCEP: ATP III (from 2001, modified in 2004), IDF (2005), IDF Consortium (2009), or Polish Scientific Society Consortium standards (2022) are now frequently in use. Hepatosteatosis and hepatofibrosis are commonly mentioned aspects of metabolic syndrome that greatly increase the likelihood of developing complications. The objective of the study was to assess different diagnostic criteria for metabolic syndrome based on the prevalence of liver steatosis and fibrosis. A retrospective analysis was conducted on the medical data of 2102 patients. Out of all the single criteria, meeting the obesity criterion based on waist circumference showed the highest increase in the risk of hepatosteatosis (by 64-69%, depending on the definition used)-hypertriglyceridemia increased the risk of hepatofibrosis by 71%. Regardless of the specific criteria used, patients with metabolic syndrome had a 34-36% increased likelihood of developing hepatosteatosis-the probability of hepatofibrosis varied between 42% and 47% for the criteria established in 2004, 2005, and 2009, while the Polish 2022 criteria were not statistically significant (p = 0.818). It seems appropriate to establish consistent metabolic syndrome diagnostic criteria-the 2009 IDF guidelines are the most effective in assessing hepatosteatosis and fibrosis risk.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects 1 in 3-4 adult individuals and can progress to metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. Insulin resistance plays a central role in MASLD/MASH pathophysiology with higher rates of MASLD (2 in 3) and MASH with fibrosis (1 in 5) in adults with obesity and diabetes. This review summarizes the role of glucagon-like peptide-1 receptor agonists in treating MASLD/MASH. Although not approved by the Food and Drug Administration for the treatment of MASLD, this class of medication is available to treat obesity and type 2 diabetes and has been shown to reverse steatohepatitis, reduce cardiovascular risk, and is safe to use across the spectrum of MASLD with or without fibrosis.

The US Department of Veterans Affairs (VA) and the US Department of Defense (DoD) approved a joint clinical practice guideline for the management of type 2 diabetes. This was the product of a multidisciplinary guideline development committee composed of clinicians from both the VA and the DoD and was overseen by the VA/DoD Evidence Based Practice Work Group. The development process conformed to the standards for trustworthy guidelines as established by the National Academy of Medicine. The guideline development committee developed 12 key questions to guide an evidence synthesis. An independent third party identified relevant randomized controlled trials and systematic reviews that were published from January 2016 through April 2022. This evidence synthesis served as the basis for drafting recommendations. Twenty-six recommendations were generated and rated by the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. Two algorithms were developed to guide clinical decision-making. This synopsis summarizes key aspects of the VA/DoD Clinical Practice Guideline for diabetes in 5 areas: prediabetes, screening for co-occurring conditions, diabetes self-management education and support, glycemic treatment goals, and pharmacotherapy. The guideline is designed to help clinicians and patients make informed treatment decisions to optimize health outcomes and quality of life and to align with patient-centered goals of care.

To assess frequency of evidence-based management (EBM) of metabolic dysfunction-associated steatotic liver disease (MASLD) in patients with type 2 diabetes (T2D), and to examine for racial/ethnic disparities in the receipt of EBM.

We conducted a cross-sectional analysis of patients with T2D and presumptive MASLD in an academic health care system between 2019 and 2021. Presumptive MASLD was defined as at least 1 alanine aminotransferase value ≥30 U/L with exclusions for alcohol overuse, viral hepatitis, liver transplantation, chemotherapy use, and liver disease other than MASLD. We calculated the proportion of patients receiving EBM, defined as a composite of liver ultrasound, transient elastography, or hepatology evaluation. We also examined the association between race/ethnicity and EBM via a logistic regression model.

Our sample included 6532 patients; mean age was 58.0 (SD 13.1), 41.7% were female and 3.9%, 26.6%, 58.7%, and 5.8% were of Latino/a/x ethnicity, non-Latino (NL) Black race, NL White race, and NL Asian race, respectively. Rates of EBM were low overall (11.5%), with lower odds of EBM in NL Black versus NL White patients (adjusted odds ratio 0.75; 95% confidence interval 0.59, 0.96). Odds of hepatology evaluation and placement of MASLD diagnosis codes were also lower in NL Black versus NL White patients.

Racial disparities exist in the receipt of EBM among patients with T2D and presumptive MASLD. These findings highlight the need for research to identify drivers of disparities, and to support development of clinical interventions that equitably facilitate EBM of MASLD in patients with T2D.

Fatty liver plays a pivotal role in the pathogenesis of the metabolic syndrome and type 2 diabetes. According to an updated classification, any individual with liver steatosis and one or more features of the metabolic syndrome, without excess alcohol consumption or other known causes of steatosis, has metabolic dysfunction-associated steatotic liver disease (MASLD). Up to 60-70% of all individuals with type 2 diabetes have MASLD. However, the prevalence of advanced liver fibrosis in type 2 diabetes remains uncertain, with reported estimates of 10-20% relying on imaging tests and likely overestimating the true prevalence. All stages of MASLD impact prognosis but fibrosis is the best predictor of all-cause and liver-related mortality risk. People with type 2 diabetes face a two- to threefold increase in the risk of liver-related death and hepatocellular carcinoma, with 1.3% progressing to severe liver disease over 7.7 years. Because reliable methods for detecting steatosis are lacking, MASLD mostly remains an incidental finding on imaging. Regardless, several medical societies advocate for universal screening of individuals with type 2 diabetes for advanced fibrosis. Proposed screening pathways involve annual calculation of the Fibrosis-4 (FIB-4) index, followed by a secondary test such as transient elastography (TE) for intermediate-to-high-risk individuals. However, owing to unsatisfactory biomarker specificity, these pathways are expected to channel approximately 40% of all individuals with type 2 diabetes to TE and 20% to tertiary care, with a false discovery rate of up to 80%, raising concerns about feasibility. There is thus an urgent need to develop more effective strategies for surveying the liver in type 2 diabetes. Nonetheless, weight loss through lifestyle changes, pharmacotherapy or bariatric surgery remains the cornerstone of management, proving highly effective not only for metabolic comorbidities but also for MASLD. Emerging evidence suggests that fibrosis biomarkers may serve as tools for risk-based targeting of weight-loss interventions and potentially for monitoring response to therapy.

Tobacco exposure is known to be associated with a higher prevalence and incidence of liver diseases. Cotinine, a metabolite of nicotine, is a typical indicator of tobacco exposure. However, the relationship of serum cotinine levels with hepatic steatosis and liver fibrosis remains controversial and these relationships need more research to explored in American teenagers. Cross-sectional data included 1433 participants aged 12-19 from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2020 were thoroughly used for this study. The linear relationships between serum cotinine levels and the Liver Stiffness Measurement (LSM) and Controlled Attenuation Parameter (CAP) were examined using multiple linear regression models. Subgroup analysis, interaction tests, and nonlinear interactions were also carried out. Serum cotinine levels > 2.99 ng/ml [β = 0.41 (0.07, 0.76), p = 0.018] and 0.05-2.99 ng/ml [β = 0.24 (0.00, 0.49), p = 0.048] showed a significant positive connection with LSM in multivariate linear regression analysis when compared to serum cotinine levels ≤ 0.05 ng/ml (p for trend = 0.006). Moreover, we discovered an inverted U-shaped association of log2-transformed cotinine with LSM with an inflection point of 4.53 using a two-stage linear regression model. However, according to multiple regression analysis, serum cotinine and CAP did not significantly correlate (p = 0.512). In conclusion, this study demonstrated that smoking cessation and keep away from secondhand smoking may beneficial for liver health in American teenagers.

Sepsis remains a major health challenge worldwide, characterized by a dysregulated host response to infection, leading to high mortality and morbidity in intensive care units (ICUs). The Fibrosis 4 (FIB-4) index, originally developed to assess liver fibrosis in hepatitis C patients, has recently been explored for its potential prognostic value in sepsis patients.

this study retrospectively analyzed 309 sepsis patients admitted to the Internal Medicine and An-aesthesia ICUs between 12 December 2021 and 15 December 2023 to investigate the relationship between FIB-4 levels, the Acute Physiology and Chronic Health Evaluation (APACHE), the Sequential Organ Failure Assessment (SOFA), and clinical outcomes.

This study found that higher FIB-4 measurements were statistically significantly associated with increased 28-day mortality, with a cut-off value of 4.9, providing a sensitivity of 54.92% and specificity of 74.25%. Logistic regression analysis indicated that elevated FIB-4 levels were a significant predictor of early mortality, suggesting that the FIB-4 index could serve as a valuable prognostic tool in assessing the severity and prognosis of sepsis patients.

by elucidating the potential role of the FIB-4 index in sepsis prognosis, this study contributes to the ongoing efforts to improve risk stratification and enhance patient care in sepsis management.

Non-Alcoholic-Fatty-Liver-Disease (NAFLD) is the most common cause of chronic liver disease in Western countries; closely linked to obesity and type 2 diabetes (T2DM), it is an additional cardiovascular risk factor. The aim of this study is to investigate the prevalence of NAFLD at T2DM onset.

122 newly diagnosed T2DM patients were enroled; NAFLD was diagnosed using ultrasound and fibrosis risk calculated with an FIB4-score. Intermediate and high-risk patients were referred to a hepatologist and underwent transient elastography (TE).

At T2DM diagnosis, 25% of patients were overweight, 47% were obese; ultrasound steatosis was present in 79% of patients; the average FIB-4 score was 1.4 (0.7). The NAFLD population was characterised by higher presence of obesity (60%, p 0.06); hypertension (56%, p 0.00); AST (26.3 (23.6) UI/L; p 0.00); ALT (49.3(41.0) UI/L p 0.00); FIB-4 score (1.6 (0.8); p 0.00). Among patients referred to a hepatologist, at TE, 65% had severe steatosis, 22% significant fibrosis and 25% advanced fibrosis.

This is the first proposal of a NAFLD screening model at T2DM diagnosis. The high prevalence of fibrosis found at the early stage T2DM confirms the compelling need for early management of NAFLD through cost-effective screening and long-term monitoring algorithms.

In the present narrative review, we have summarized evidence on the pharmacological treatment of non-alcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD). We start by reviewing the epidemiology of the condition and its close association with obesity and type 2 diabetes. We then discuss how randomized-controlled trials are performed following guidance from regulatory agencies, including differences and similarities between requirements of the US Food and Drug Administration and the European Medicine Agency. Difficulties and hurdles related to limitations of liver biopsy, a large number of screening failures in recruiting patients, as well as unpredictable response rates in the placebo group are evaluated. Finally, we recapitulate the strategies employed for potential drug treatments of this orphan condition. The first is to repurpose drugs that originally targeted T2DM and/or obesity, such as pioglitazone, glucagon-like peptide 1 receptor agonists (liraglutide and semaglutide), multi-agonists (tirzepatide and retatrutide), and sodium-glucose transporter 2 inhibitors. The second is to develop drugs specifically targeting NAFLD/MASLD. Among those, we focused on resmetirom, fibroblast growth factor 21 analogs, and lanifibranor, as they are currently in Phase 3 of their clinical trial development. While many failures have characterized the field of pharmacological treatment of NAFLD/MASLD in the past, it is likely that approval of the first treatments is near. As occurs in many chronic conditions, combination therapy might lead to better outcomes. In the case of non-alcoholic steatohepatitis, we speculate that drugs treating underlying metabolic co-morbidities might play a bigger role in the earlier stages of disease, while liver-targeting molecules will become vital in patients with more advanced disease in terms of inflammation and fibrosis.

Despite being one of the major drivers of diabetes incidence, the degree of insulin resistance in patients with type 2 diabetes (T2D) is not usually evaluated in clinical practice or in large epidemiologic studies.

To identify a model of insulin sensitivity using widely available clinical and laboratory parameters in patients with T2D and evaluate its association with all-cause and cardiovascular mortality.

One hundred forty patients with T2D underwent a euglycemic hyperinsulinemic clamp to measure total body glucose disposal rate (mg kg-1 minute-1). We used demographic, clinical, and common laboratory parameters to estimate insulin sensitivity (IS) via stepwise linear regression on 85 patients (training cohort) and validated it in the remaining 55 (validation cohort). The identified equation was then applied to 3553 patients with T2D from the 1999-2010 cycles of the National Health and Nutrition Examination Survey (NHANES) to evaluate its association with all-cause and cardiovascular mortality up to December 2015.

The best model included triglycerides, gamma glutamyl transpeptidase, albumin excretion rate, and body mass index. The identified IS score correlated well with the clamp-derived glucose disposal rate in both the training (r = 0.77, P < .001) and the validation (r = 0.74, P < .001) cohorts. In the NHANES cohort, after a median follow-up of 8.3 years, 1054 patients died, 265 of cardiovascular causes. In a multivariable Cox proportional hazard model adjusted for age, sex, race-ethnicity, education, cigarette smoke, total cholesterol, chronic kidney disease, blood pressure, prevalent cardiovascular disease, and alcohol consumption, a higher estimated IS was associated with a lower risk of both all-cause and cardiovascular mortality.

We propose a new model of IS in patients with T2D based on readily available clinical and laboratory data. Its potential applications are in both diagnosis as well as prognostication.

To identify individuals with incidental fatty liver disease (FLD), and to evaluate its prevalence, metabolic co-morbidities and impact on follow-up.

We leveraged the data-lake of Helsinki Uusimaa Hospital district (Finland) with a population of 1.7 million (specialist and primary care). A phrase recognition script on abdominal imaging reports (2008-2020) identified/excluded FLD or cirrhosis; we extracted ICD-codes, laboratory and BMI data.

Excluding those with other liver diseases, the prevalence of FLD was 29% (steatosis yes/no, N=61,271/155,521; cirrhosis, N=3502). The false positive and negative rates were 5-6%. Only 1.6% of the FLD cases had the ICD code recorded and 32% had undergone full clinical evaluation for associated co-morbidities. Of the 35-65-year-old individuals with FLD, 20% had diabetes, 42% prediabetes and 28% a high liver fibrosis index. FLD was independently predicted by diabetes (OR 1.56, CI 1.46-1.66, p = 2.3 * 10^-41), BMI (1.46, 1.42-1.50, p = 1.7 * 10^-154) and plasma triglyceride level (1.5, 1.43-1.57, p = 3.5 * 10^-68). Alanine aminotransferase level mildly increased (1.12, 1.08-1.16, p = 2.2 * 10^-9) and high age decreased the risk (0.92, 0.89-0.94, p = 4.65*10^-09). Half of the cases had normal ALT.

The incidental radiological finding of FLD is reliable and associated with metabolic risks but largely ignored, although it should lead to metabolic and hepatic follow-up.

Liver fibrosis is the strongest predictor of liver-related mortality in many chronic liver diseases. NT-ProBNP is independently associated with cardiovascular mortality in general population settings. Here, we evaluate the relative contribution of non-invasively identified liver fibrosis and NT-ProBNP on all-cause and cardiovascular mortality in patients with metabolic (dysfunction)-associated steatotic liver disease (MASLD).

Serum NT-ProBNP levels were measured in 4229 patients with MASLD from the general population without a known history of heart failure that participated in the 1999-2004 cycles of the National Health and Nutrition Examination Survey. Presence of liver fibrosis was estimated using the Fibrosis-4 index (FIB-4). We applied Cox proportional hazard models adjusted for cardiovascular risk factors to evaluate the association between NT-ProBNP and FIB-4 levels and all-cause and cardiovascular mortality through December 2019. Mortality was lower for participants with normal levels of both biomarkers, intermediate if a single biomarker was elevated and highest when both were above the chosen threshold. In the multivariable-adjusted models, both elevated FIB-4 (≥2.67) and elevated NT-ProBNP levels (≥125 pg/ml) were independently associated with higher risks of all-cause mortality (HR 2.2, 95 % CI 1.5-3.2 and HR 1.6, 95 % CI 1.4-2.0, respectively) and cardiovascular mortality (HR 2.1, 95 % CI 1.2-3.7 and HR 2.1, 95 % CI 1.5-2.9, respectively). The associations remained consistent in subgroup analyses based on sex, obesity and age.

Both FIB-4 and NT-ProBNP are independently associated with higher mortality in patients with MASLD. Their combined use might prove useful to risk-stratify patients in clinical practice.

The bidirectional relationship between type 2 diabetes and (non-alcoholic fatty liver disease) NAFLD is indicated by the higher prevalence and worse disease course of one condition in the presence of the other, but also by apparent beneficial effects observed in one, when the other is improved. This is partly explained by their belonging to a multisystemic disease that includes components of the metabolic syndrome and shared pathogenetic mechanisms. Throughout the progression of NAFLD to more advanced stages, complex systemic and local metabolic derangements are involved. During fibrogenesis, a significant metabolic reprogramming occurs in the hepatic stellate cells, hepatocytes, and immune cells, engaging carbohydrate and lipid pathways to support the high-energy-requiring processes. The natural history of NAFLD evolves in a variable and dynamic manner, probably due to the interaction of a variable number of modifiable (diet, physical exercise, microbiota composition, etc.) and non-modifiable (genetics, age, ethnicity, etc.) risk factors that may intervene concomitantly, or subsequently/intermittently in time. This may influence the risk (and rate) of fibrosis progression/regression. The recognition and control of the factors that determine a rapid progression of fibrosis (or its regression) are critical, as the fibrosis stages are associated with the risk of liver-related and all-cause mortality.

Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), can promote the development of cirrhosis, hepatocellular carcinoma, cardiovascular disease, and type 2 diabetes. Similarly, type 2 diabetes confers the greatest risk for the development of NASH, especially when associated with obesity. Although lifestyle changes are critical to success, early implementation of pharmacological treatments for obesity and type 2 diabetes are essential to treat NASH and avoid disease progression. This article reviews current guidance regarding the use of pharmacological agents such as pioglitazone, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors in the setting of NAFLD and NASH. It also reviews the latest information on new drugs currently being investigated for the treatment of NASH.

The incidence of non-B and non-C hepatocellular carcinoma (NBNC-HCC) is increasing globally. Metabolically associated fatty liver disease (MAFLD) has been a contributing factor to this rising trend in NBNC-HCC incidence. The monocyte-to-high-density lipoprotein-cholesterol ratio (MHR) is a new prognostic marker that connects systemic inflammation with disorders of lipid metabolism. Therefore, MHR may be a potential prognostic predictor of patients with MAFLD-related HCC (MAFLD-HCC). This study aims to investigate the relationship between the MHR and prognosis of patients with MAFLD-HCC and construct a novel prognostic prediction tool for MAFLD-HCC.

This retrospective study of patients with MAFLD-HCC included training (n = 112) and internal validation (n = 37) cohorts. Univariate and multivariate Cox proportional hazard regression analysis was conducted to identify independent risk factors of survival. A visual nomogram was constructed to assess the performance of the two groups. Furthermore, receiver operating characteristic (ROC) curves and calibration curves were used to verify the prognostic discriminative ability of this nomogram, even in the MHR, ALBI grade, and MHR-ALBI model.

Univariate and multivariate analyses revealed that extrahepatic metastases, Vascular invasion, Barcelona staging B, C, D, elevated ALBI Grade 3, C-reactive protein (CRP), and MHR were independent risk factors for the prognosis of MAFLD-HCC. Moreover, calibration plots showed good discrimination and consistency when the significant factors were entered into the nomogram. Meanwhile, the MHR strongly correlated with the prognosis of cancer under a background of MAFLD-HCC, with a sensitivity of 88.89% and a specificity of 79.61%. Importantly, the performance of the MHR alone (AUC = 86.2) was not only superior to the ALBI grade (AUC = 63.8) but was comparable to the combination of MHR and ALBI (AUC = 88.5).

The novel nomogram demonstrated good value in predicting the overall survival of patients with MAFLD-HCC. The MHR may be a potential predictor of prognosis.

To investigate the association of four insulin resistance (IR) indicators with hepatic steatosis and fibrosis in patients with metabolic syndrome (MetS), as well as to compare the diagnostic value of these indicators in identifying hepatic steatosis and fibrosis in individuals with MetS.

This cross-sectional study used the data from the National Health and Nutrition Examination Survey 2017-2018. IR indicators included homeostasis model assessment of IR (HOMA-IR), triglyceride/glucose (TyG) index, triglyceride glucose-waist-to-height ratio (TyG-WHtR), and metabolic score for IR (METS-IR). The main endpoints of this study were hepatic steatosis and hepatic fibrosis. Weighted univariate and multivariate logistic regression models were employed to evaluate the association between four IR indicators and both hepatic steatosis, hepatic fibrosis. The efficacy of various IR indicators in the detection of hepatic steatosis and hepatic fibrosis were assessed using receiver operating characteristics curve (ROC).

A total of 876 participants with MetS were enrolled. Among the participants, hepatic steatosis was observed in 587 MetS individuals, while hepatic fibrosis was identified in 151 MetS individuals. In multivariate logistic regression model, HOMA-IR, TyG, TyG-WHtR, and METS-IR were related to the increased odd of hepatic steatosis. Additionally, HOMA-IR, TyG-WHtR, and METS-IR were associated with increased odd of hepatic fibrosis. According to the ROC analysis, the area under the curve (AUC) of the TyG-WHtR (AUC = 0.705, 95%CI: 0.668-0.743) was higher than HOMA-IR (AUC = 0.693, 95%CI: 0.656-0.730), TyG (AUC = 0.627, 95%CI: 0.587-0.666), and METS-IR (AUC = 0.685, 95%CI: 0.648-0.722) for identifying hepatic steatosis of MetS patients. Likewise, TyG-WHtR was also higher than HOMA-IR, TyG, and METS-IR for identifying hepatic fibrosis of MetS patients.

HOMA-IR, TyG-WHtR, and METS-IR may be associated with the risk of hepatic steatosis and fibrosis among the U.S. adult population with MetS. In addition, TyG-WHtR may have a good predictive value for hepatic steatosis and hepatic fibrosis.

As morbidity and mortality related to potentially preventable liver diseases are on the rise globally, early detection of liver fibrosis offers a window of opportunity to prevent disease progression. Early detection of non-alcoholic fatty liver disease allows for initiation and reinforcement of guidance on bodyweight management, risk stratification for advanced liver fibrosis, and treatment optimisation of diabetes and other metabolic complications. Identification of alcohol-related liver disease provides the opportunity to support patients with detoxification and abstinence programmes. In all patient groups, identification of cirrhosis ensures that patients are enrolled in surveillance programmes for hepatocellular carcinoma and portal hypertension. When considering early detection strategies, success can be achieved from applying ad-hoc screening for liver fibrosis in established frameworks of care. Patients with type 2 diabetes are an important group to consider case findings of advanced liver fibrosis and cirrhosis, as up to 19% have advanced fibrosis (which is ten times higher than the general population) and almost 70% have non-alcoholic fatty liver disease. Additionally, patients with type 2 diabetes with alcohol use disorders have the highest proportion of liver-related morbidity of people with type 2 diabetes generally. Patients with type 2 diabetes receive an annual diabetes review as part of their routine clinical care, in which the health of many organs are considered. Yet, liver health is seldom included in this review. This Viewpoint argues that augmenting the existing risk stratification strategy with an additional liver health check provides the opportunity to detect advanced liver fibrosis, thereby opening a window for early interventions to prevent end-stage liver disease and its complications, including hepatocellular carcinoma.