Optimal cut-offs of transient elastography and magnetic resonance elastography in diagnosing advanced liver fibrosis in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis.

Background/aims: Opinions differ regarding transient elastography and magnetic resonance elastography (TE/MRE) cut-offs for diagnosing advanced fibrosis (AF) in patients with non-alcoholic fatty liver disease (NAFLD). We investigated the diagnostic performance and optimal cut-off values of TE and MRE for diagnosing AF. Methods: Literature databases, including Medline, EMBASE, Cochrane Library, and KoreaMed, were used to identify relevant studies published up to June 13, 2023. We selected studies evaluating TE and MRE regarding the degree of liver fibrosis using liver biopsy as the reference. The sensitivity, specificity, and area under receiver operating characteristics curves (AUCs) of the pooled data for TE and MRE for each fibrosis stage and optimal cut-offs for AF were investigated. Results: A total of 19,199 patients from 63 studies using TE showed diagnostic AUC of 0.83(95% confidence interval: 0.80-0.86), 0.83(0.80-0.86), 0.87(0.84-0.90), and 0.94(0.91-0.96) for ≥F1, ≥F2, ≥F3, and F4 stages, respectively. Similarly, 1,484 patients from 14 studies using MRE showed diagnostic AUC of 0.89(0.86-0.92), 0.92(0.89-0.94), 0.89(0.86-0.92), and 0.94(0.91-0.96) for ≥F1, ≥F2, ≥F3, and F4 stages respectively. The diagnostic AUC for AF using TE was highest at 0.90 with a cut-off of 7.1-7.9 kPa, and that of MRE was highest at 0.94 with a cut-off of 3.62-3.8 kPa. Conclusions: TE(7.1-7.9 kPa) and MRE(3.62-3.8 kPa) with the suggested cut-offs showed favorable accuracy for diagnosing AF in patients with NAFLD. This result will serve as a basis for clinical guidelines for non-invasive tests and differential diagnosis of AF.

Disparities for Hispanic Adults With Metabolic Dysfunction-associated Steatotic Liver Disease in the United States: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Prevalence and severity of metabolic dysfunction-associated steatotic liver disease (MASLD) is reported to be higher in Hispanic adults in the United States (U.S.), although rates vary substantially across studies and have increased given the evolving obesity epidemic. This systematic review and meta-analysis quantifies MASLD disease burden and severity in contemporary cohorts to characterize health disparities experienced by adult Hispanic individuals in the U.S. METHODS: We searched the MEDLINE, Embase, and Cochrane databases per the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Studies from 2010 to December 2023 were included to capture data representative of current populations given the obesity epidemic. Studies from overlapping cohorts were excluded. Meta-analyses were conducted using random-effects models to estimate pooled prevalence and relative risk (RR) with 95% confidence intervals (CIs). RESULTS: We identified 22 studies, comprising 756,088 subjects, of which 62,072 were Hispanic. The pooled prevalence in U.S. Hispanic adults was 41% (95% CI, 30%-52%) for MASLD, 61% (95% CI, 39%-82%) for metabolic dysfunction-associated steatohepatitis (MASH), 27% (95% CI, 15%-39%) for MASH-associated advanced fibrosis (AF), and 5% (95% CI, 1%-8%) for MASH cirrhosis. Compared with non-Hispanic adults, Hispanic adults had a RR of 1.50 (95% CI, 1.32-1.69) for MASLD, 1.42 (95% CI, 1.04-1.93) for MASH, 1.37 (95% CI, 0.96-1.96) for MASH-associated AF, and 0.93 (95% CI, 0.49-1.77) for MASH cirrhosis. CONCLUSION: Health disparities for U.S. Hispanic adults continue to worsen with significantly higher relative risk of MASLD and MASH compared with non-Hispanic adults. Public health efforts to optimize screening and care delivery for the adult Hispanic population are urgently needed.

Identifying and Linking Patients At Risk for MASLD with Advanced Fibrosis to Care in Primary Care.

BACKGROUND AND AIMS: Severity of fibrosis is the driver of liver-related outcomes in metabolic dysfunction-associated steatotic liver disease (MASLD), and non-invasive testing such as fibrosis-4 (FIB-4) score is utilized for risk stratification. We aimed to determine if primary care patients at risk for MASLD and advanced fibrosis were evaluated with subsequent testing. A secondary aim was to determine if at-risk patients with normal aminotransferases had advanced fibrosis. METHODS: Primary care patients at increased risk for MASLD with advanced fibrosis (n = 91,914) were identified using previously established criteria. Patients with known alternative/concomitant etiology of liver disease or cirrhosis were excluded. The study cohort included patients with calculated FIB-4 score in 2020 (n = 52,006), and stratified into low, indeterminate, and high likelihood of advanced fibrosis. Among those at indeterminate/high risk, rates of subsequent testing were measured. RESULTS: Risk stratification with FIB-4 characterized 77% (n = 40,026) as low risk, 17% (n = 8847) as indeterminate, and 6% (n = 3133) as high risk. Among indeterminate/high-risk patients (n = 11,980), 78.7% (n = 9433) had aminotransferases within normal limits, 0.95% (n = 114) had elastography, and 8.2% (n = 984) were referred for subspecialty evaluation. CONCLUSION: In this cohort of primary care patients at risk for MASLD with fibrosis, the FIB-4 score identified a substantial proportion of indeterminate/high-risk patients, the majority of which had normal aminotransferase levels. Low rates of subsequent testing were observed. These data suggest that a majority of patients at increased risk for liver-related outcomes remain unrecognized and highlight opportunities to facilitate their identification.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD)-related advanced fibrosis and cirrhosis in the United States population utilizing AGILE 3 + and AGILE 4 scores: analysis of the NHANES 2017-2018 cycle.

BACKGROUND: Studies attempted to estimate MASLD-related advanced fibrosis (AF) and cirrhosis (MC) prevalence utilized tests with low positive predictive value (PPV) which overestimates prevalence. AGILE3 + and 4 scores were developed to increase the PPV of both; respectively. In this study, we used these scores to assess the prevalence of AF and MC. METHODS: Participants aged ≥ 18 years with VCTE exam in the NHANES 2017-2018 cycle were included. We excluded pregnant women, patients with excessive alcohol intake, hepatitis B/C, and ALT or AST > 500 IU/L. MASLD was defined with CAP score > 248 dB/m. MASLD subjects with AGILE 3 + score of ≥ 0.68 and AGILE 4 score of ≥ 0.57 were considered to have advanced fibrosis and cirrhosis; respectively. AGILE 3 + of 0.45-0.67 and AGILE 4 of 0.25-0.57 were grey zone, whereas AGILE 3 + < 0.45 and AGILE 4 < 0.25 were considered a rule-out. RESULTS: 1244 subjects were included in the final analysis. The Median age was 53 (51.4-54.6) years, 55.6% were male, median BMI was 33.8 kg/m2 and 41.1% had T2DM. Based on AGILE 3+, 80.3% of the MASLD population were at low risk for AF and 11.5% were in grey zone. The prevalence of AF due to MASLD was 8.1% corresponding to 4.5 million Americans. Based on AGILE 4 score, 96.5% of the MASLD population were at low risk for cirrhosis and 2.4% were in the grey zone. The prevalence of MASLD-cirrhosis was 1.1% corresponding to 610,000 Americans. CONCLUSION: Our results suggest that approximately 4.5 million people in the U.S. have AF and 0.6 million have cirrhosis due to MASLD.

Global prevalence of advanced fibrosis in patients with type 2 diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND AND AIM: Patients with type 2 diabetes mellitus (T2DM) face a heightened susceptibility to advanced fibrosis, a condition linked to adverse clinical outcomes. However, reported data on liver fibrosis severity among individuals with T2DM vary significantly across studies with diverse characteristics. This meta-analysis aimed to estimate the global prevalence of advanced fibrosis among T2DM patients. METHODS: A comprehensive systematic search of the EMBASE and MEDLINE databases from inception to November 2022 was conducted to identify studies assessing advanced fibrosis in individuals with T2DM. Random-effects models were utilized to calculate point estimates of prevalence, accompanied by 95% confidence interval (CI). Meta-regression with subgroup analysis was employed to address heterogeneity. RESULTS: We identified 113 eligible studies involving 244,858 individuals from 29 countries. Globally, the prevalence of advanced fibrosis among T2DM patients was 19.5% (95% CI 16.8-22.4%). Regionally, the prevalence rates were as follows: 60.5% in West Asia (95% CI 50.3-70.4%), 24.4% in South Asia (95% CI 16.2-33.7%), 20.1% in East Asia (95% CI 14.7-26.1%), 20.0% in Europe (95% CI 15.8-24.6%), 15.8% in North America (95% CI 11.0-21.3%), and 11.3% in South America (95% CI 6.2-17.5%). The prevalence of advanced fibrosis varied notably based on the study setting and diagnostic methodology employed. Meta-regression models highlighted that 45.13% of the observed heterogeneity could be attributed to combined diagnostic modality and study setting. CONCLUSIONS: Globally, approximately one fifth of the T2DM population presents advanced fibrosis, with prevalence differing across geographical regions. Our findings underscore the need for effective strategies to alleviate its global burden.

Association Between Serum Zinc and Non-Alcoholic Fatty Liver Disease and Advanced Liver Fibrosis: NHANES 2011-2016.

Limited and inconclusive evidence exists regarding the correlation between serum zinc levels and non-alcoholic fatty liver disease (NAFLD) and advanced fibrosis. The objective of this cross-sectional study was to investigate the association between serum zinc concentration and both NAFLD and advanced liver fibrosis among the United States (US) adults. 3398 subjects from National Health and Nutrition Examination Survey (NHANES) 2011-2016 were included. Serum zinc concentration was measured by inductively coupled plasma dynamic reaction cell mass spectrometry (ICP-DRC-MS). NAFLD was diagnosed with Hepatic Steatosis Index (HSI), and advanced fibrosis risk was assessed by NAFLD Fibrosis Score (NFS). Weighted logistic regression and restricted cubic splines (RCS) were used to examine the association between serum zinc concentration and NAFLD and advanced fibrosis. Linear trend tests were conducted by incorporating the median of serum zinc quartiles as a continuous variable in the models. We employed sensitivity analysis and subgroup analysis to enhance the robustness of our results. The results from the RCS regression revealed no evident nonlinear relationship between serum zinc concentration and the presence of NAFLD and advanced fibrosis (p-nonlinear > 0.05). Compared with those in the lowest quartile (Q1) of serum zinc concentrations, the odds ratios (95% confidence intervals) of NAFLD were 1.49 (0.89,2.49) in Q2, 0.99 (0.68,1.45) in Q3, and 2.00 (1.40,2.86) in Q4 (p-trend = 0.002). Similarly, the odds ratios (95% confidence intervals) for advanced fibrosis in Q2-4 compared to Q1 were 0.86 (0.50,1.47), 0.60 (0.26,1.39), and 0.41 (0.21,0.77), respectively (p-trend = 0.006). Subgroup analyses and sensitivity analyses reinforce the same conclusion. The investigation revealed a positive linear relationship between serum zinc concentrations and the probability of developing NAFLD. Conversely, an inverse correlation was observed between serum zinc concentrations and the incidence of advanced liver fibrosis among individuals diagnosed with NAFLD.

Integrating genetic and socioeconomic data to predict the progression of nonalcoholic fatty liver disease.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease globally, with an estimated prevalence exceeding 25%. Variants in the PNPLA3 and HSD17B13 genes have been a focus of investigations surrounding the etiology and progression of NAFLD and are believed to contribute to a greater burden of disease experienced by Hispanic Americans. However, little is known about socioeconomic factors influencing NAFLD progression or its increased prevalence among Hispanics. MATERIALS AND METHODS: We cross-sectionally analyzed 264 patients to assess the role of genetic and socioeconomic variables in the development of advanced liver fibrosis in individuals at risk for NAFLD. RESULTS: Adjusting for age, sex, body mass index, and PNPLA3 genotype, lacking a college degree was associated with 3.3 times higher odds of advanced fibrosis (95% confidence interval [CI]: 1.21-8.76, p = 0.019), an effect comparable to that of possessing the major PNPLA3 risk variant. Notably, the effect of PNPLA3 genotype on advanced fibrosis was attenuated to nonsignificance following adjustment for education and other socioeconomic markers. The effect of the protective HSD17B13 variant, moreover, diminished after adjustment for education (odds ratio [OR]: 0.39 [95% CI: 0.13-1.16, p = 0.092]), while lower education continued to predict advanced fibrosis following multivariable adjustment with an OR of 8.0 (95% CI: 1.91-33.86, p = 0.005). DISCUSSION: Adjusting for education attenuated the effects of genotype and Hispanic ethnicity on liver fibrosis, suggesting that social factors-rather than genes or ethnicity-may be driving disease severity within some populations. Findings reveal the importance of including socioenvironmental controls when considering the role of genetics or ethnicity in complex disease.

Association of AST/ALT ratio with 90-day outcomes in patients with acute exacerbation of chronic liver disease: a prospective multicenter cohort study in China.

Background and aim: A high aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio is associated with liver injury in liver disease; however, no data exist regarding its relationship with 90-day prognosis in patients with acute exacerbation of chronic liver disease. Methods: In this study, 3,758 participants (955 with advanced fibrosis and 2,803 with cirrhosis) from the CATCH-LIFE cohort in China were included. The relationships between different AST/ALT ratios and the risk of adverse 90-day outcomes (death or liver transplantation) were determined in patients with cirrhosis or hepatitis B virus (HBV)-associated advanced fibrosis, respectively. Results: In the patients with HBV-associated advanced fibrosis, the risk of 90-day adverse outcomes increased with AST/ALT ratio; after adjusting for all confounding factors, the risk of adverse 90-day outcomes was the highest when AST/ALT ratio was more than 1.08 (OR = 6.91 [95% CI = 1.789-26.721], p = 0.005), and the AST/ALT ratio of >1.9 accelerated the development of adverse outcomes. In patients with cirrhosis, an AST/ALT ratio > 1.38 increased the risk of adverse 90-day outcomes in all univariables (OR = 1.551 [95% CI = 1.216-1.983], p < 0.001) and multivariable-adjusted analyses (OR = 1.847 [95% CI = 1.361-2.514], p < 0.001), and an elevated AST/ALT ratio (<2.65) accelerated the incidence of 90-day adverse outcomes. An AST/ALT ratio of >1.38 corresponded with a more than 20% incidence of adverse outcomes in patients with cirrhosis. Conclusion: The AST/ALT ratio is an independent risk factor for adverse 90-day outcomes in patients with cirrhosis and HBV-associated advanced fibrosis. The cutoff values of the AST/ALT ratio could help clinicians monitor the condition of patients when making clinical decisions.

Noninvasive tests maintain high accuracy for advanced fibrosis in chronic hepatitis B patients with different nomenclatures of steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a new nomenclature proposed in 2023. We aimed to compare the diagnostic efficacy of noninvasive tests (NITs) for advanced fibrosis under different nomenclatures in patients with chronic hepatitis B (CHB). A total of 844 patients diagnosed with CHB and concurrent steatotic liver disease (SLD) by liver biopsy were retrospectively enrolled and divided into four groups. The performances of fibrosis-4 (FIB-4), gamma-glutamyl transpeptidase to platelet ratio index (GPRI), aspartate aminotransferase to platelet ratio index (APRI), and liver stiffness measurement (LSM) were compared among the four groups. The four NITs showed similar diagnostic efficacy for nonalcoholic fatty liver disease (NAFLD), MASLD, and metabolic dysfunction-associated fatty liver disease (MAFLD) in patients with CHB with advanced fibrosis. LSM showed the most stable accuracy for NAFLD (AUC = 0.842), MASLD (AUC = 0.846), and MAFLD (AUC = 0.863) compared with other NITs (p < 0.05). Among the four NITs, APRI (AUC = 0.841) and GPRI (AUC = 0.844) performed best in patients with CHB & MetALD (p < 0.05). The cutoff value for GPRI in patients with CHB & MetALD was higher than that in the other three groups, while further comparisons of NITs at different fibrosis stages showed that the median GPRI of CHB & MetALD (1.113) at F3-4 was higher than that in the CHB & MASLD group (0.508) (p < 0.05). Current NITs perform adequately in patients with CHB and SLD; however, alterations in cutoff values for CHB & MetALD need to be noted.

TyG-GGT is a Reliable Non-Invasive Predictor of Advanced Liver Fibrosis in Overweight or Obese Individuals.

BACKGROUND: Liver fibrosis is a predisposing factor for liver cancer. This study will investigate the predictive role of the Triglyceride-glucose and Gamma-glutamyl transferase index (TyG-GGT) as a non-invasive indicator of advanced liver fibrosis in individuals with obesity or overweight. METHOD: We enrolled patients who underwent metabolic and bariatric surgery as well as intraoperative liver biopsies at Zhejiang provincial people's hospital from August 2020 to March 2023. Clinical characteristics, comorbidities, laboratory data, and pathological variables of patients were collected and analysed. Then, we conducted logistics regression model to compare the performance of the TyG-GGT index with other 4 non-invasive models. RESULTS: A total of 65 patients were included in this study. 43(66.2%) of them were female, with the mean body mass index (BMI) of 39.0 ± 7.3 kg/m2. Meanwhile, 24(36.9%) patients were diagnosed with diabetes. Advanced liver fibrosis were observed in 16.9% of patients, while liver cirrhosis was found in 4.6% of patients. The multivariable logistics regression showed that TyG-GGT was an independent risk factor of advanced liver fibrosis (OR = 6.989, P = 0.049). Additionally, compared to another 4 non-invasive liver fibrosis models (NFS = 0.66, FIB4 = 0.65, METS-IR = 0.68, APRI = 0.65), TyG-GGT exhibits the highest AUC value of 0.75. CONCLUSIONS: More than one-third of patients undergoing metabolic and bariatric surgery are afflicted with nonalcoholic steatohepatitis (NASH), and a significant proportion exhibit advanced fibrosis. TyG-GGT was a potentially reliable predictor for screening individuals with overweight or obesity at high risk of advanced liver fibrosis, thus providing clinical guidance for early intervention in this targeted group.

Chronic exposure to ambient air pollution and the risk of non-alcoholic fatty liver disease: A cross-sectional study in Taiwan and Hong Kong.

BACKGROUND: Information on the relation of air pollution with non-alcoholic fatty liver disease (NAFLD) is scarce. We thus conducted a large cross-sectional study in Asia to investigate the role of air pollution in NAFLD. METHODS: We recruited 329,048 adults (mean age: 41.0 years) without other liver disease (hepatitis and cirrhosis) or excessive alcohol consumption in Taiwan and Hong Kong from 2001 to 2018. The concentrations of nitrogen dioxide (NO2) and ozone (O3) were estimated using a space-time regression model, and the concentrations of fine particulate matter (PM2.5) was evaluated using a satellite-based spatio-temporal model. NAFLD was determined using either the fatty liver index (FLI) or the hepatic steatosis index (HSI). The NAFLD-related advanced fibrosis was defined according to BARD score or the fibrosis-4 (FIB-4). A logistic regression model was adopted to explore the relationships of ambient air pollution with the odds of NAFLD and NAFLD-related advanced fibrosis. RESULTS: We found positive relationships between PM2.5 and the odds of NAFLD and advanced fibrosis, with every standard deviation (SD, 7.5 µg/m3) increases in PM2.5 exposure being associated with a 10% (95% confidence interval [CI]: 9%-11%) increment in the prevalence of NAFLD and an 8% (95% CI: 7%-9%) increment in the prevalence of advanced fibrosis. Similarly, the prevalence of NAFLD and advanced fibrosis increased by 8% (95% CI: 7%-9%) and 7% (95% CI: 6%-8%) with per SD (18.9 µg/m3) increasement in NO2 concentration, respectively. Additionally, for every SD (9.9 µg/m3) increasement in O3 concentration, the prevalence of NAFLD and advanced fibrosis decreased by 12% (95% CI: 11%-13%) and 11% (95% CI: 9%-12%), respectively. CONCLUSION: Higher ambient PM2.5 and NO2 are linked with higher odds of NAFLD and advanced fibrosis. Our findings indicate that reducing PM2.5 and NO2 concentrations may be an effective way for preventing NAFLD. Further studies on O3 are warranted.

Combination Therapy of Endoscopic Gastric Remodeling with GLP-1RA for the Treatment of MASLD.

PURPOSE: The mainstay of treatment for metabolic dysfunction-associated steatotic liver disease (MASLD) is weight loss. Endoscopic gastric remodeling (EGR) and glucagon-like peptide-1 receptor agonist (GLP-1RA) are effective weight loss therapies. This study aims to assess the effect of combining EGR with GLP-1RA on liver-related outcomes and weight profile. MATERIALS AND METHODS: This is a retrospective study of a prospectively collected registry of patients with MASLD and compensated advanced chronic liver disease (cACLD) who underwent EGR. Patients were categorized as (1) monotherapy: EGR alone and (2) combination therapy: GLP-1RA prescribed within 6 months prior to or after EGR. Outcomes included changes in noninvasive tests of hepatic fibrosis, weight profile, and insulin resistance status at 12 months. RESULTS: Thirty patients (body mass index 40.7 ± 9.3 kg/m2) were included. Of these, 12 patients (40%) underwent EGR monotherapy, and 18 patients (60%) underwent EGR + GLP-1RA combination therapy. Combination therapy group experienced greater improvements in fibrosis compared to monotherapy group (alanine aminotransferase: reduction by 55 ± 23% vs 29 ± 22% (p = 0.008), NAFLD fibrosis score: reduction by 181 ± 182% vs 30 ± 83% (p = 0.04), liver stiffness measurement on transient elastography: reduction by 54 ± 12% vs 14 ± 45% (p = 0.05)). There were greater reductions in hemoglobin A1c and homeostatic model assessment for insulin resistance in combination therapy compared to monotherapy (p < 0.05). At 12 months, the combination therapy group experienced 18.2 ± 6.6% TWL, while monotherapy group experienced 9.6 ± 3.3% TWL (p = 0.004). CONCLUSIONS: In patients with MASLD and cACLD, combination of EGR with GLP-1RA is associated with greater improvements in hepatic fibrosis, weight profile, and insulin resistance compared to EGR alone.

Development of Clinical Algorithm Utilizing Vibration-Controlled Transient Elastography to Detect Advanced Hepatic Fibrosis in Liver Transplant Recipients.

INTRODUCTION: Vibration-controlled transient elastography (VCTE) based liver stiffness measurement (LSM) is an excellent 'rule-out' test for advanced hepatic fibrosis in liver transplant (LT) recipients, however, its ability to 'rule-in' the disease is suboptimal. The study aimed to improve diagnostic performance of LSM in LT recipients. METHODS: Adult LT recipients with a liver biopsy and VCTE were included (N = 150). Sequential covering analysis was performed to create rules to identify patients at low or high risk for advanced fibrosis (stage 3-4). RESULTS: Advanced hepatic fibrosis was excluded in patients with either LSM < 7.45 kPa (n = 72) or 7.45 ≤ LSM < 12.1 kPa and time from LT < 5.6 years (n = 25). Conversely, likelihood of advanced fibrosis was 95% if patients had LSM > 14.1 and controlled attenuation parameter > 279 dB/m (n = 21). Thus, 118 (79%) were correctly identified and 32 (21%) would have required a biopsy to establish the diagnosis. Compared to previously established LSM based cutoff values of 10.5 kPa (Youden index) and 13.3 kPa (maximized specificity), the false positive rates of sequential covering analysis was 1% compared to 16.5% with LSM ≥ 10.5 kPa and 8.3% with LSM ≥ 13.3 kPa. The true positive rates were comparable at 87% for sequential covering analysis, 93% for LSM ≥ 10.5 kPa and 83% for LSM ≥ 13.3 kPa. CONCLUSION: The proposed clinical sequential covering analysis allows for better risk stratification when evaluating for advanced fibrosis in LT recipients compared to LSM alone. Additional efforts are necessary to further reduce the number of patients with indeterminate results in whom a liver biopsy may be required.

Optimal ALT threshold for the automated diagnosis of MASLD: A population-based study using iLFT.

INTRODUCTION AND OBJECTIVES: Early diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD), especially with advanced fibrosis, is crucial due to the increased risk of complications and mortality. Serum alanine aminotransferase (ALT) is commonly used; however, many patients have normal ranges (<55 U/L) who may remain undetected. We investigated the clinical implications of a lower ALT cut-off (>30 U/L) using intelligent liver function testing (iLFT) to identify MASLD patients with and without advanced fibrosis in primary care. MATERIALS AND METHODS: All patients entering the iLFT diagnostic pathway had liver aetiological screening investigations if ALT >30 U/L. In those with MASLD the proportions with and without advanced fibrosis at different ALT thresholds: 31-41 U/L, 42-54 U/L and ≥55 U/L were compared. RESULTS: 16,373 patients underwent iLFT between March 2016 to April 2022. 762 (5 %) patients had MASLD with abnormal fibrosis scores, while 908 (6 %) had MASLD with normal fibrosis scores. 428 (56 %) patients were assessed in liver clinics, where 169 (39 %) had evidence of fibrosis. Of these, 22 (13 %) had ALT 31-41 U/L, 31 (18 %) had ALT 42-54 U/L and 116 (69 %) had ALT ≥55 U/L. 145 (86 %) patients had advanced fibrosis or cirrhosis, where 20 (14 %) had ALT 31-41 U/L, 28 (19 %) had ALT 42-54 U/L and 97 (67 %) had ALT ≥55 U/L. CONCLUSIONS: 33 % of MASLD patients with advanced fibrosis or cirrhosis had ALT 31-54 U/L, who would have been missed using the conventional ALT range. This suggests that lowering the ALT cut-off improves diagnosis of MASLD with advanced fibrosis in primary care.

Steatotic liver disease predicts cardiovascular disease and advanced liver fibrosis: A community-dwelling cohort study with 20-year follow-up.

BACKGROUND: Steatotic liver disease (SLD) has emerged as new nomenclature to increase awareness and reflect the pathophysiology of the disease better. We investigated the risk of advanced fibrosis and cardiovascular disease (CVD) in SLD using data derived from a Korean prospective cohort. METHODS: We defined SLD using the fatty liver index (FLI) and identified advanced fibrosis with the age-adjusted Fibrosis-4 Index. SLD was further subcategorized into metabolic dysfunction-associated SLD (MASLD), MASLD with increased alcohol intake (MetALD), and alcohol-associated liver disease (ALD). FINDINGS: The Ansung-Ansan cohort of the Korean Genome and Epidemiology study, following 9497 participants from 2002 to 2020, included 3642 (38.3%) with MASLD, 424 (4.5%) with MetALD, and 207 (2.1%) with ALD. During the median follow-up of 17.5 years, CVD risk was higher in those with MASLD (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.12-1.45; P < 0.001), MetALD (HR, 1.88; 95% CI, 1.33-2.65; P < 0.001), and ALD (HR, 1.95; 95% CI, 1.01-3.77; P < 0.001) than in those without SLD, after adjusting for conventional risk factors. Notably, CVD risk was higher in the MetALD than in the MASLD group (P = 0.027). In the MASLD group, the number of cardiometabolic risk factors (CMRFs) correlated positively with CVD risk (HR, 1.34; 95% CI, 1.24-1.45; P < 0.001 for trend). Among the CMRFs, hypertension (HR, 1.94; 95% CI, 1.63-2.31; P < 0.001) was the predominant contributor to CVD. The MASLD (HR, 1.39; 95% CI, 1.25-1.55; P < 0.001), MetALD (HR, 1.75; 95% CI, 1.38-2.23; P < 0.001), and ALD (HR, 2.00; 95% CI, 1.30-3.07; P = 0.002) groups had a higher risk of advanced fibrosis than did the non-SLD group (P < 0.001 for trend). INTERPRETATION: Our study provides new insight into hepatic and cardiovascular outcomes related to SLD subtypes. The risk of CVD increased in the order of no SLD, MASLD, and MetALD. The SLD subcategories, considering CMRFs and alcohol intake, outperformed traditional fatty liver categorizations in predicting CVD risk. The proposed SLD terminology could impact clinical practice, warranting further exploration of the heterogeneity of clinical outcomes among SLD subtypes.

Prevalence and Determinants of Liver Disease in Relatives of Italian Patients With Advanced MASLD.

BACKGROUND & AIMS: Metabolic dysfunction associated steatotic liver disease (MASLD) has a strong genetic component. The aim of this study was to examine noninvasively the prevalence of MASLD and of advanced fibrosis in relatives of patients with advanced MASLD and the risk factors for liver involvement, with a focus on the contribution of common genetic risk variants. METHODS: We prospectively enrolled 98 consecutive probands with advanced fibrosis and/or hepatocellular carcinoma caused by MASLD and 160 nontwin first-degree relatives noninvasively screened for MASLD and advanced fibrosis at 4 Italian centers. We evaluated common genetic determinants and polygenic risk scores of liver disease. RESULTS: Among relatives, prevalence of MASLD was 56.8% overall, whereas advanced fibrosis was observed in 14.4%. At multivariable analysis in relatives, MASLD was associated with body mass index (odds ratio [OR], 1.31 [1.18-1.46]) and tended to be associated with diabetes (OR, 5.21 [0.97-28.10]), alcohol intake (OR, 1.32 [0.98-1.78]), and with female sex (OR, 0.54 [0.23-1.15]), whereas advanced fibrosis was associated with diabetes (OR, 3.13 [1.16-8.45]) and nearly with body mass index (OR, 1.09 [1.00-1.19]). Despite that the PNPLA3 risk variant was enriched in probands (P = .003) and overtransmitted to relatives with MASLD (P = .045), evaluation of genetic risk variants and polygenic risk scores was not useful to guide noninvasive screening of advanced fibrosis in relatives. CONCLUSIONS: We confirmed that about 1 in 7 relatives of patients with advanced MASLD has advanced fibrosis, supporting clinical recommendations to perform family screening in this setting. Genetic risk variants contributed to liver disease within families but did not meaningfully improve fibrosis risk stratification.

Machine-learning model comprising five clinical indices and liver stiffness measurement can accurately identify MASLD-related liver fibrosis.

BACKGROUND & AIMS: aMAP score, as a hepatocellular carcinoma risk score, is proven to be associated with the degree of chronic hepatitis B-related liver fibrosis. We aimed to evaluate the ability of aMAP score for metabolic dysfunction-associated steatotic liver disease (MASLD; formerly NAFLD)-related fibrosis diagnosis and establish a machine-learning (ML) model to improve the diagnostic performance. METHODS: A total of 946 biopsy-proved MASLD patients from China and the United States were included in the analysis. The aMAP score, demographic/clinical indices and liver stiffness measurement (LSM) were included in seven ML algorithms to build fibrosis diagnostic models in the training set (N = 703). The performance of ML models was evaluated in the external validation set (N = 125). RESULTS: The AUROCs of aMAP versus fibrosis-4 index (FIB-4) and aspartate aminotransferase-platelet ratio (APRI) in cirrhosis and advanced fibrosis were (0.850 vs. 0.857 [P = 0.734], 0.735 [P = 0.001]) and (0.759 vs. 0.795 [P = 0.027], 0.709 [P = 0.049]). When using dual cut-off values, aMAP had a smaller uncertainty area and higher accuracy (26.9%, 86.6%) than FIB-4 (37.3%, 85.0%) and APRI (59.0%, 77.3%) in cirrhosis diagnosis. The seven ML models performed satisfactorily in most cases. In the validation set, the ML model comprising LSM and 5 indices (including age, sex, platelets, albumin and total bilirubin used in aMAP calculator), built by logistic regression algorithm (called LSM-plus model), exhibited excellent performance. In cirrhosis and advanced fibrosis detection, the LSM-plus model had higher accuracy (96.8%, 91.2%) than LSM alone (86.4%, 67.2%) and Agile score (76.0%, 83.2%), respectively. Additionally, the LSM-plus model also displayed high specificity (cirrhosis: 98.3%; advanced fibrosis: 92.6%) with satisfactory AUROC (0.932, 0.875, respectively) and sensitivity (88.9%, 82.4%, respectively). CONCLUSIONS: The aMAP score is capable of diagnosing MASLD-related fibrosis. The LSM-plus model could accurately identify MASLD-related cirrhosis and advanced fibrosis.

Age, BMI, and Type 2 Diabetes Modify the Relationship Between PNPLA3 and Advanced Fibrosis in Children and Adults With NAFLD.

BACKGROUND & AIMS: PNPLA3 G-allele is an important determinant of disease severity in nonalcoholic fatty liver disease (NAFLD). Here, we investigated the effect of age, body mass index (BMI), and type 2 diabetes mellitus (T2DM) on the relationship between PNPLA3 G-allele and advanced fibrosis in adults and children with histologically characterized NAFLD. METHODS: A total of 1047 children and 2057 adults were included. DNA was genotyped for rs738409 in duplicate. Primary outcome of interest was advanced fibrosis (fibrosis stage ≥3). Regression analyses were performed after controlling for relevant covariates. An additive model was used to assess the effect of PNPLA3 G-allele (CC vs CG vs GG). RESULTS: PNPLA3 G-allele was significantly associated with advanced fibrosis in children (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16-2.09) and adults (OR, 1.55; 95% CI, 1.16-1.54). Across the cohort, older age significantly increased the risk for advanced fibrosis for PNPLA3 CC (OR, 1.019; 95% CI, 1.013-1.026), CG (OR, 1.024; 95% CI, 1.018-1.030), and GG (OR, 1.03; 95% CI, 1.023-1.037) genotypes. BMI significantly increased the relationship between PNPLA3 genotypes and advanced fibrosis in children and adults. A BMI of 30 kg/m2 was the cutoff beyond which PNPLA3 G-allele had exponential effect on the risk for advanced fibrosis in children and adults. T2DM significantly worsened the relationship between PNPLA3 G-allele and advanced fibrosis in children and adults (interaction P < .01 for both). CONCLUSIONS: Age, BMI, and T2DM modify the risk of advanced fibrosis associated with PNPLA3 G-allele. Preventing or reversing T2DM and obesity in persons carrying PNPLA3 G-allele may lower the risk for advanced fibrosis in NAFLD.

Peginterferon plus ribavirin and sustained virological response rate in HCV-related advanced fibrosis: a real life study

Background: Tolerance and response to antiviral HCV treatment is poor in advanced fibrosis. The aim of this study was to assess SVR rate and its predictive factors in HCV advanced fibrosis patients treated in real life with full dose PEG-IFN plus RBV and to evaluate the adverse events related to treatment. Methods: A multicentric, retrospective study was conducted at six university hospitals. METAVIR F3 and F4 HCV monoinfected patients who were treated with PEG-IFN and RBV had their data analyzed. A stepwise logistic regression analysis was performed to identify the variables independently related to SVR. Adverse events were recorded during treatment. Results: 308 patients were included, 75% genotype 1 and 23% genotype 3. METAVIR F3 was present in 39% and F4 in 61% of patients. The median Child Pugh score for F4 patients was 5 (5–9). The global SVR rate was 34%, 11% were relapsers and 55% were nonresponders. SVR rates were similar between patients treated with PEG-IFN alfa 2a or alfa 2b (p = 0.24). SVR rates according to Child–Pugh score were 26% (Child A) and 18% (Child B). The independent factors related to SVR in F4 patients were genotype 3, RVR and fewer Child Pugh score points. Treatment interruption occurred in 31% patients and death occurred in 1.9%, all with liver cirrhosis. Conclusion: Treatment of HCV in patients with advanced fibrosis should not be postponed. However, a very careful evaluation of cirrhotic patients must be performed before treatment is indicated and careful monitoring is required during treatment. .