Obesity increases the risk of hepatic fibrosis in young adults with type 2 diabetes mellitus: the need to screen.

OBJECTIVE: The objective of this study was to determine the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in young compared with older adults. METHODS: Individuals (n = 1420) with (63%) and without type 2 diabetes mellitus (T2D; 37%) who attended internal medicine clinics and did not have a known history of MASLD underwent laboratory evaluation and transient elastography to assess for hepatic steatosis and fibrosis. Magnetic resonance elastography and liver biopsy were recommended when indicated. RESULTS: A total of 243 participants were ages <45 years, and 1177 were ages ≥45 years. Obesity, T2D, and metabolic syndrome were highly prevalent in young adults. Frequencies of steatosis and fibrosis were high in young adults (50.2% and 7.5% vs. older adults 52.7% and 9.9%, respectively) and were significantly higher in those with both obesity and T2D (71.1% and 15.7%, respectively; p < 0.01). In young adults, T2D and obesity were the strongest risk factors for hepatic fibrosis (odds ratios 4.33 [95% CI: 1.37-13.68] and 1.16 [95% CI: 1.07-1.25], respectively; p < 0.05). CONCLUSIONS: There is a high prevalence of clinically significant hepatic fibrosis in young adults with cardiometabolic risk factors. Up to one in seven young adults with obesity and T2D had clinically significant hepatic fibrosis on elastography. This highlights the need to screen young adults with cardiometabolic risk factors for MASLD for early detection and intervention.

Decreases in cT1 and liver fat content reflect treatment-induced histological improvements in MASH.

BACKGROUND & AIMS: MRI biomarkers of liver disease are robust and reproducible alternatives to liver biopsy. Emerging data suggest that absolute reduction in iron corrected T1 (cT1) of ≥ 80 ms and relative reduction in liver fat content of 30% reflect histological improvement. We aimed to validate the associations of changes to these noninvasive biomarkers with histological improvement, specifically the resolution of steatohepatitis. METHODS: A retrospective analysis of participants from three interventional clinical trials who underwent multiparametric MRI to measure liver cT1 and liver fat content (LFC) (LiverMultiScan) alongside biopsies at baseline and end of study. Responders were defined as those achieving resolution of steatohepatitis with no worsening in fibrosis. Differences in the magnitude of change in cT1 and LFC between responders and non-responders was assessed. RESULTS: Individual patient data from 150 participants were included. There was a significant decrease in liver cT1 (-119 ms vs. -49 ms) and liver fat content (-65% vs. -29%) in responders compared to non-responders (P < .001) respectively. The diagnostic accuracy to identify responders was 0.72 (AUC) for both. The Youden's index for cT1 to separate responders from non-responders was -82 ms and for liver fat was a 58% relative reduction. Those achieving a ≥ 80 ms reduction in cT1 were 5-times more likely to achieve histological response (sens 0.68; spec 0.70). Those achieving a 30% relative reduction in liver fat were ∼4 times more likely to achieve a histological response (sens 0.77; spec 0.53). CONCLUSIONS: These results, from three combined drug trials, demonstrate that changes in multiparametric MRI markers of liver health (cT1 and PDFF) can predict histological response for steatohepatitis following therapeutic intervention. IMPACT AND IMPLICATIONS: There is great interest in identifying suitable biomarkers that can be used to replace liver biopsy, or to identify those patients who would benefit from one, in both the clinical management of MASH and in drug development. We investigated the utility of two MRI-derived non-invasive tests, iron corrected T1 mapping (cT1) and liver fat content from proton density fat fraction (PDFF), to predict histological improvement in patients who had undergone experimental treatment for MASH. Using data from 150 people who participated in one of three clinical trials, we observed that a reduction in cT1 by over 80 ms and a relative reduction in PDFF of over 58% were the optimal thresholds for change that predicted resolution of steatohepatitis. PDFF as a marker of liver fat, and cT1 as a specific measure of liver disease activity, are both effective at identifying those who are likely responding to drug interventions and experiencing improvements in overall liver health. CLINICAL TRIAL NUMBER(S): NCT02443116, NCT03976401, NCT03551522.

Detecting altered hepatic lipid oxidation by MRI in an animal model of MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence is increasing annually and affects over a third of US adults. MASLD can progress to metabolic dysfunction-associated steatohepatitis (MASH), characterized by severe hepatocyte injury, inflammation, and eventual advanced fibrosis or cirrhosis. MASH is predicted to become the primary cause of liver transplant by 2030. Although the etiology of MASLD/MASH is incompletely understood, dysregulated fatty acid oxidation is implicated in disease pathogenesis. Here, we develop a method for estimating hepatic ß-oxidation from the metabolism of [D15]octanoate to deuterated water and detection with deuterium magnetic resonance methods. Perfused livers from a mouse model of MASLD reveal dysregulated hepatic ß-oxidation, findings that corroborate in vivo imaging. The high-fat-diet-induced MASLD mouse studies indicate that decreased ß-oxidative efficiency in the fatty liver could serve as an indicator of MASLD progression. Furthermore, our method provides a clinically translatable imaging approach for determining hepatic ß-oxidation efficiency.

Insulin resistance is an integral feature of MASLD even in the presence of PNPLA3 variants.

Background & Aims: It has been postulated that carriers of PNPLA3 I148M (CG [Ile/Met] or GG [Met/Met]) develop metabolic dysfunction-associated steatotic liver disease (MASLD) in the absence of insulin resistance or metabolic syndrome. However, the relationship between insulin resistance and MASLD according to the PNPLA3 allele has not been carefully assessed. Methods: A total of 204 participants were recruited and underwent PNPLA3 genotyping, an oral glucose tolerance test, liver proton magnetic resonance spectroscopy and percutaneous liver biopsy if diagnosed with MASLD. A subgroup of patients (n = 55) had an euglycemic hyperinsulinemic clamp with glucose tracer infusion. Results: As expected, patients with the CG/GG genotype had worse intrahepatic triglyceride content and worse liver histology. However, regardless of PNPLA3 genotype, patients with a diagnosis of MASLD had severe whole-body insulin resistance (Matsuda index, an estimation of insulin resistance in glucose metabolic pathways) and fasting and postprandial adipose tissue insulin resistance (Adipo-IR index and free fatty acid suppression during the oral glucose tolerance test, respectively, as measures of insulin resistance in lipolytic metabolic pathways) compared to patients without MASLD. Moreover, for the same amount of liver fat accumulation, insulin resistance was similar in patients with genotypes CC vs. CG/GG. In multiple regression analyses, A1c and Adipo-IR were associated with the presence of MASLD and advanced liver fibrosis, independently of PNPLA3 genotype. Conclusions: PNPLA3 variant carriers with MASLD are equally insulin resistant as non-carriers with MASLD at the level of the liver, muscle, and adipose tissue. This calls for reframing "PNPLA3 MASLD" as an insulin-resistant condition associated with increased hepatic susceptibility to metabolic insults, such as obesity or diabetes, wherein early identification and aggressive intervention are warranted to reverse metabolic dysfunction and prevent disease progression. Impact and implications: It has been proposed that the PNPLA3 G allele is associated with the presence of metabolic dysfunction-associated steatotic liver disease (MASLD) in the absence of insulin resistance. However, our results suggest that regardless of PNPLA3 alleles, the presence of insulin resistance is necessary for the development of MASLD. This calls for reframing patients with "PNPLA3 MASLD" not as insulin sensitive, but on the contrary, as an insulin-resistant population with increased hepatic susceptibility to metabolic insults, such as obesity or diabetes.

The impact of stigma on quality of life and liver disease burden among patients with nonalcoholic fatty liver disease.

Background & Aims: Patients with nonalcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD) face a multifaceted disease burden which includes impaired health-related quality of life (HRQL) and potential stigmatization. We aimed to assess the burden of liver disease in patients with NAFLD and the relationship between experience of stigma and HRQL. Methods: Members of the Global NASH Council created a survey about disease burden in NAFLD. Participants completed a 35-item questionnaire to assess liver disease burden (LDB) (seven domains), the 36-item CLDQ-NASH (six domains) survey to assess HRQL and reported their experience with stigmatization and discrimination. Results: A total of 2,117 patients with NAFLD from 24 countries completed the LDB survey (48% Middle East and North Africa, 18% Europe, 16% USA, 18% Asia) and 778 competed CLDQ-NASH. Of the study group, 9% reported stigma due to NAFLD and 26% due to obesity. Participants who reported stigmatization due to NAFLD had substantially lower CLDQ-NASH scores (all p <0.0001). In multivariate analyses, experience with stigmatization or discrimination due to NAFLD was the strongest independent predictor of lower HRQL scores (beta from -5% to -8% of score range size, p <0.02). Experience with stigmatization due to obesity was associated with lower Activity, Emotional Health, Fatigue, and Worry domain scores, and being uncomfortable with the term "fatty liver disease" with lower Emotional Health scores (all p <0.05). In addition to stigma, the greatest disease burden as assessed by LDB was related to patients' self-blame for their liver disease. Conclusions: Stigmatization of patients with NAFLD, whether it is caused by obesity or NAFLD, is strongly and independently associated with a substantial impairment of their HRQL. Self-blame is an important part of disease burden among patients with NAFLD. Impact and implications: Patients with nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), may experience impaired health-related quality of life and stigmatization. Using a specifically designed survey, we found that stigmatization of patients with NAFLD, whether it is caused by obesity or the liver disease per se, is strongly and independently associated with a substantial impairment of their quality of life. Physicians treating patients with NAFLD should be aware of the profound implications of stigma, the high prevalence of self-blame in the context of this disease burden, and that providers' perception may not adequately reflect patients' perspective and experience with the disease.

Guideline-based management of metabolic dysfunction-associated steatotic liver disease in the primary care setting.

BACKGROUND: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide. Primary care providers play a critical role in the screening, diagnosis, and management of MASLD and/or metabolic dysfunction-associated steatohepatitis (MASH), though they can face challenges in this setting, particularly where healthcare resources are limited and barriers to care exist. To address these challenges, several guidelines have been developed to provide evidence-based recommendations for the clinical assessment and management of patients with MASLD/MASH. AIMS: To provide a unified, simple-to-understand, practical guide for MASLD screening, diagnosis, and management based on current guideline recommendations, for use by primary care providers in daily practice. METHODS: Evidence-based recommendations from several international guidelines were summarized, focusing on the similarities and differences between them. RESULTS: Recommendations are broadly aligned across the guidelines, but several key differences are evident. Practical guidance is provided on screening, identifying target populations for risk stratification, initial evaluation of individuals with suspected MASLD, surveillance, risk stratification and referral, as well as approaches to the management of MASLD and associated comorbidities, with specific considerations for the primary care setting. CONCLUSIONS: Primary care providers are ideally placed to identify at-risk individuals, implement evidence-based interventions to prevent the development of fibrosis and cirrhosis, and effectively manage comorbidities. Equipping primary care providers with the necessary knowledge and tools to effectively manage MASLD/MASH may help to improve patient outcomes and reduce the burden of liver disease.

Making Sense of the Nonalcoholic Fatty Liver Disease Clinical Practice Guidelines: What Clinicians Need to Know.

Standards of care summarized in clinical practice guidelines for nonalcoholic fatty liver disease (NAFLD) offer clinicians a streamlined diagnostic and management approach based on the best available evidence. These recommendations have changed a great deal in recent years; today, there is a clear focus on screening for the early identification and risk stratification of patients at high risk of steatohepatitis and clinically significant fibrosis to promote timely referrals to specialty care when needed. This article reviews and provides the rationale for current guidelines for NAFLD screening, diagnosis, treatment, and monitoring and addresses barriers to providing evidence-based NAFLD care and how to overcome them. The current paradigm of care calls for primary care clinicians and specialists to work together, within a multidisciplinary care team familiar with obesity and diabetes care, to provide comprehensive management of these complex patients.

Role of Insulin Resistance in the Development of Nonalcoholic Fatty Liver Disease in People With Type 2 Diabetes: From Bench to Patient Care.

Insulin resistance is implicated in both the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and its progression from steatosis to steatohepatitis, cirrhosis, and even hepatocellular carcinoma, which is known to be more common in people with type 2 diabetes. This article reviews the role of insulin resistance in the metabolic dysfunction observed in obesity, type 2 diabetes, atherogenic dyslipidemia, and hypertension and how it is a driver of the natural history of NAFLD by promoting glucotoxicity and lipotoxicity. The authors also review the genetic and environmental factors that stimulate steatohepatitis and fibrosis progression and their relationship with cardiovascular disease and summarize guidelines supporting the treatment of NAFLD with diabetes medications that reduce insulin resistance, such as pioglitazone or glucagon-like peptide 1 receptor agonists.

Pharmacological Approaches to Nonalcoholic Fatty Liver Disease: Current and Future Therapies.

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.

A global action agenda for turning the tide on fatty liver disease.

BACKGROUND AND AIMS: Fatty liver disease is a major public health threat due to its very high prevalence and related morbidity and mortality. Focused and dedicated interventions are urgently needed to target disease prevention, treatment, and care. APPROACH AND RESULTS: We developed an aligned, prioritized action agenda for the global fatty liver disease community of practice. Following a Delphi methodology over 2 rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the action priorities using Qualtrics XM, indicating agreement using a 4-point Likert-scale and providing written feedback. Priorities were revised between rounds, and in R2, panelists also ranked the priorities within 6 domains: epidemiology, treatment and care, models of care, education and awareness, patient and community perspectives, and leadership and public health policy. The consensus fatty liver disease action agenda encompasses 29 priorities. In R2, the mean percentage of "agree" responses was 82.4%, with all individual priorities having at least a super-majority of agreement (> 66.7% "agree"). The highest-ranked action priorities included collaboration between liver specialists and primary care doctors on early diagnosis, action to address the needs of people living with multiple morbidities, and the incorporation of fatty liver disease into relevant non-communicable disease strategies and guidance. CONCLUSIONS: This consensus-driven multidisciplinary fatty liver disease action agenda developed by care providers, clinical researchers, and public health and policy experts provides a path to reduce the prevalence of fatty liver disease and improve health outcomes. To implement this agenda, concerted efforts will be needed at the global, regional, and national levels.

Serum identification of at-risk MASH: The metabolomics-advanced steatohepatitis fibrosis score (MASEF).

BACKGROUND: Early identification of those with NAFLD activity score ≥ 4 and significant fibrosis (≥F2) or at-risk metabolic dysfunction-associated steatohepatitis (MASH) is a priority as these patients are at increased risk for disease progression and may benefit from therapies. We developed and validated a highly specific metabolomics-driven score to identify at-risk MASH. METHODS: We included derivation (n = 790) and validation (n = 565) cohorts from international tertiary centers. Patients underwent laboratory assessment and liver biopsy for metabolic dysfunction-associated steatotic liver disease. Based on 12 lipids, body mass index, aspartate aminotransferase, and alanine aminotransferase, the MASEF score was developed to identify at-risk MASH and compared to the FibroScan-AST (FAST) score. We further compared the performance of a FIB-4 + MASEF algorithm to that of FIB-4 + liver stiffness measurements (LSM) by vibration-controlled transient elastography (VCTE). RESULTS: The diagnostic performance of the MASEF score showed an area under the receiver-operating characteristic curve, sensitivity, specificity, and positive and negative predictive values of 0.76 (95% CI 0.72-0.79), 0.69, 0.74, 0.53, and 0.85 in the derivation cohort, and 0.79 (95% CI 0.75-0.83), 0.78, 0.65, 0.48, and 0.88 in the validation cohort, while FibroScan-AST performance in the validation cohort was 0.74 (95% CI 0.68-0.79; p = 0.064), 0.58, 0.79, 0.67, and 0.73, respectively. FIB-4+MASEF showed similar overall performance compared with FIB-4 + LSM by VCTE ( p = 0.69) to identify at-risk MASH. CONCLUSION: MASEF is a promising diagnostic tool for the assessment of at-risk MASH. It could be used alternatively to LSM by VCTE in the algorithm that is currently recommended by several guidance publications.

Artificial intelligence-assisted digital pathology for non-alcoholic steatohepatitis: current status and future directions.

The worldwide prevalence of non-alcoholic steatohepatitis (NASH) is increasing, causing a significant medical burden, but no approved therapeutics are currently available. NASH drug development requires histological analysis of liver biopsies by expert pathologists for trial enrolment and efficacy assessment, which can be hindered by multiple issues including sample heterogeneity, inter-reader and intra-reader variability, and ordinal scoring systems. Consequently, there is a high unmet need for accurate, reproducible, quantitative, and automated methods to assist pathologists with histological analysis to improve the precision around treatment and efficacy assessment. Digital pathology (DP) workflows in combination with artificial intelligence (AI) have been established in other areas of medicine and are being actively investigated in NASH to assist pathologists in the evaluation and scoring of NASH histology. DP/AI models can be used to automatically detect, localise, quantify, and score histological parameters and have the potential to reduce the impact of scoring variability in NASH clinical trials. This narrative review provides an overview of DP/AI tools in development for NASH, highlights key regulatory considerations, and discusses how these advances may impact the future of NASH clinical management and drug development. This should be a high priority in the NASH field, particularly to improve the development of safe and effective therapeutics.

Global survey of stigma among physicians and patients with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Patients with fatty liver disease may experience stigma from the disease or comorbidities. In this cross-sectional study, we aimed to understand stigma among patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and healthcare providers. METHODS: Members of the Global NASH Council created two surveys about experiences/attitudes toward NAFLD and related diagnostic terms: a 68-item patient and a 41-item provider survey. RESULTS: Surveys were completed by 1,976 patients with NAFLD across 23 countries (51% Middle East/North Africa [MENA], 19% Europe, 17% USA, 8% Southeast Asia, 5% South Asia) and 825 healthcare providers (67% gastroenterologists/hepatologists) across 25 countries (39% MENA, 28% Southeast Asia, 22% USA, 6% South Asia, 3% Europe). Of all patients, 48% ever disclosed having NAFLD/NASH to family/friends; the most commonly used term was "fatty liver" (88% at least sometimes); "metabolic disease" or "MAFLD" were rarely used (never by >84%). Regarding various perceptions of diagnostic terms by patients, there were no substantial differences between "NAFLD", "fatty liver disease (FLD)", "NASH", or "MAFLD". The most popular response was being neither comfortable nor uncomfortable with either term (56%-71%), with slightly greater discomfort with "FLD" among the US and South Asian patients (47-52% uncomfortable). Although 26% of patients reported stigma related to overweight/obesity, only 8% reported a history of stigmatization or discrimination due to NAFLD. Among providers, 38% believed that the term "fatty" was stigmatizing, while 34% believed that "nonalcoholic" was stigmatizing, more commonly in MENA (43%); 42% providers (gastroenterologists/hepatologists 45% vs. 37% other specialties, p = 0.03) believed that the name change to metabolic dysfunction-associated steatotic liver disease (or MASLD) might reduce stigma. Regarding the new nomenclature, the percentage of providers reporting "steatotic liver disease" as stigmatizing was low (14%). CONCLUSIONS: The perception of NAFLD stigma varies among patients, providers, geographic locations and sub-specialties. IMPACT AND IMPLICATIONS: Over the past decades, efforts have been made to change the nomenclature of nonalcoholic fatty liver disease (NAFLD) to better align with its underlying pathogenetic pathways and remove any potential stigma associated with the name. Given the paucity of data related to stigma in NAFLD, we undertook this global comprehensive survey to assess stigma in NAFLD among patients and providers from around the world. We found there is a disconnect between physicians and patients related to stigma and related nomenclature. With this knowledge, educational programs can be developed to better target stigma in NAFLD among all stakeholders and to provide a better opportunity for the new nomenclature to address the issues of stigma.