Steatotic liver disease.

Steatotic liver disease is the overarching term for conditions characterised by abnormal lipid accumulation in the liver (liver or hepatic steatosis). Steatotic liver disease encompasses what was previously termed non-alcoholic fatty liver disease (NAFLD), which is now called metabolic dysfunction-associated steatotic liver disease (MASLD). Additionally, steatotic liver disease includes alcohol-related liver disease (ALD) and MetALD, the new classification for the overlap between MASLD and ALD, and rare causes of liver steatosis. Cirrhosis is globally the 11th leading cause of death, and steatotic liver disease has become the leading cause of cirrhosis in the EU and USA. Steatotic liver disease affects around 30% of the global population and is mainly driven by obesity, type 2 diabetes, and alcohol intake, but only a minor proportion with steatotic liver disease progress to cirrhosis. The presence and progression of liver fibrosis led by hepatic inflammation is the main predictor of liver-related death across the entire spectrum of steatotic liver diseases. A combination of recent advancements of widely available biomarkers for early detection of liver fibrosis together with considerable advancements in therapeutic interventions offer the possibility to reduce morbidity and mortality in patients with steatotic liver disease. This Seminar covers the recent reclassification of steatotic liver disease and how it reflects clinical practice and prognosis. For early detection of liver fibrosis, we propose a collaborative diagnostic framework between primary care and liver specialists. Lastly, we discuss current best practices for managing steatotic liver disease, we explore therapeutic targets across the spectrum of steatotic liver diseases, and we review the pipeline of drugs in development for MASLD.

Further decompensation in cirrhosis: Results of a large multicenter cohort study supporting Baveno VII statements.

BACKGROUND AND AIMS: The prognostic weight of further decompensation in cirrhosis is still unclear. We investigated the incidence of further decompensation and its effect on mortality in patients with cirrhosis. APPROACH AND RESULTS: Multicenter cohort study. The cumulative incidence of further decompensation (development of a second event or complication of a decompensating event) was assessed using competing risks analysis in 2028 patients. A 4-state model was built: first decompensation, further decompensation, liver transplant, and death. A cause-specific Cox model was used to assess the adjusted effect of further decompensation on mortality. Sensitivity analyses were performed for patients included before or after 1999. In a mean follow-up of 43 months, 1192 patients developed further decompensation and 649 died. Corresponding 5-year cumulative incidences were 52% and 35%, respectively. The cumulative incidences of death and liver transplant after further decompensation were 55% and 9.7%, respectively. The most common further decompensating event was ascites/complications of ascites. Five-year probabilities of state occupation were 24% alive with first decompensation, 21% alive with further decompensation, 7% alive with a liver transplant, 16% dead after first decompensation without further decompensation, 31% dead after further decompensation, and <1% dead after liver transplant. The HR for death after further decompensation, adjusted for known prognostic indicators, was 1.46 (95% CI: 1.23-1.71) ( p <0.001). The significant impact of further decompensation on survival was confirmed in patients included before or after 1999. CONCLUSIONS: In cirrhosis, further decompensation occurs in ~60% of patients, significantly increases mortality, and should be considered a more advanced stage of decompensated cirrhosis.

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.

Long-term liver-related outcomes and liver stiffness progression of statin usage in steatotic liver disease.

BACKGROUND: Statins have multiple benefits in patients with metabolic-associated steatotic liver disease (MASLD). AIM: To explore the effects of statins on the long-term risk of all-cause mortality, liver-related clinical events (LREs) and liver stiffness progression in patients with MASLD. METHODS: This cohort study collected data on patients with MASLD undergoing at least two vibration-controlled transient elastography examinations at 16 tertiary referral centres. Cox regression analysis was performed to examine the association between statin usage and long-term risk of all-cause mortality and LREs stratified by compensated advanced chronic liver disease (cACLD): baseline liver stiffness measurement (LSM) of ≥10 kPa. Liver stiffness progression was defined as an LSM increase of ≥20% for cACLD and from <10 kPa to ≥10 or LSM for non-cACLD. Liver stiffness regression was defined as LSM reduction from ≥10 kPa to <10 or LSM decrease of ≥20% for cACLD. RESULTS: We followed up 7988 patients with baseline LSM 5.9 kPa (IQR 4.6-8.2) for a median of 4.6 years. At baseline, 40.5% of patients used statins, and cACLD was present in 17%. Statin usage was significantly associated with a lower risk of all-cause mortality (adjusted HR=0.233; 95% CI 0.127 to 0.426) and LREs (adjusted HR=0.380; 95% CI 0.268 to 0.539). Statin usage was also associated with lower liver stiffness progression rates in cACLD (HR=0.542; 95% CI 0.389 to 0.755) and non-cACLD (adjusted HR=0.450; 95% CI 0.342 to 0.592), but not with liver stiffness regression (adjusted HR=0.914; 95% CI 0.778 to 1.074). CONCLUSIONS: Statin usage was associated with a relatively lower long-term risk of all-cause mortality, LREs and liver stiffness progression in patients with MASLD.

Agile scores in MASLD and ALD: External validation and their utility in clinical algorithms.

BACKGROUND & AIMS: Agile scores, including liver stiffness measurements (LSM) and routine clinical/laboratory biomarkers, have been developed for advanced fibrosis (F≥3) and cirrhosis (F4), respectively, in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). We independently validated the diagnostic accuracy of these scores in MASLD, alcohol-related liver disease (ALD) and chronic hepatitis B or C (CHB/C) and assessed them in clinical algorithms with FIB-4 and LSM. METHODS: We included 4,243 patients (MASLD: 912, ALD: 386, CHB: 597, CHC: 2,348) with LSM, liver biopsy and laboratory tests within 6 months. FIB-4, Agile 3+ and Agile 4 scores were calculated. RESULTS: For F≥3, the diagnostic accuracy of Agile 3+ and LSM were similar in MASLD (AUC: 0.86 vs. 0.86, p = 0.831) and ALD (0.92 vs. 0.94, p = 0.123). For cirrhosis, Agile 4 was similar to LSM in MASLD (0.89 vs. 0.90, p = 0.412) and ALD (0.94 vs. 0.95, p = 0.513). Agile 3+/4 performed worse than LSM in CHB/C. Using predefined dual thresholds of 90% sensitivity/specificity, correct classification rates in MASLD were 66% vs. 61% using Agile 3+ vs. LS dual cut-offs and 71% vs. 67% in ALD, respectively. When using Agile 3+ or LSM as a second step after FIB-4 >1.3, correct classification rates were higher with Agile 3+ than LSM, both for MASLD (75% vs. 71%) and ALD (76% vs. 72%), with fewer indeterminate results. Positive agreement of LSM and Agile 3+/4 significantly increased the specificity of a diagnosis of advanced fibrosis/cirrhosis. CONCLUSION: Agile 3+ and Agile 4 have equal diagnostic accuracy with LSM in both MASLD and ALD but result in fewer indeterminate results. Sequential use of FIB-4 and Agile 3+/4 or concurrent Agile 3+/4 and LSM can be used to further optimize F≥3 diagnosis. IMPACT AND IMPLICATIONS: As of today, it is accepted that there will be no single non-invasive test or an isolated cut-off for identifying patients with advanced chronic liver disease. Here, we confirmed that Agile 3+ and Agile 4 scores are useful alternatives to simple liver stiffness measurement in diagnosing advanced fibrosis/cirrhosis in steatotic liver disease, but they do not perform as well in chronic viral hepatitis. Agile scores can help optimize the diagnosis of advanced fibrosis/cirrhosis in a dual cut-off strategy by reducing the number of indeterminate results either alone or in a sequential strategy after FIB-4. The combination of Agile scores and liver stiffness measurement can further increase our confidence in a positive diagnosis of advanced fibrosis/cirrhosis. These novel combination strategies can be useful tools to predict the likelihood of advanced stages of liver disease with the highest possible accuracy in a secondary/tertiary healthcare setting.

Cost-Effectiveness of the Baveno VI Criteria Compared With Endoscopy for High-Risk Varices in Patients With Child-Pugh A Cirrhosis.

BACKGROUND & AIMS: Although upper gastrointestinal endoscopy (EGD) remains the gold standard for detecting varices in cirrhosis, the Baveno VI criteria proposed a combination of transient elastography and platelet count that could rule out high-risk varices, therefore sparing the need for an endoscopy, with significant potential cost savings. We performed a cost-effectiveness analysis of the Baveno VI criteria compared with EGD in the diagnosis of high-risk varices in cirrhosis. METHODS: We built an analytical decision model to estimate the cost and benefits of using the Baveno VI criteria compared with EGD in patients with Child-Pugh A cirrhosis. The analysis was performed from the UK National Health Service perspective, over 1, 5, and 20 years. A Markov model was populated with data from published evidence. Outcomes were measured in terms of quality-adjusted life years (QALYs) and avoided deaths. The analyses were repeated for Canada and Spain, using relevant cost inputs. RESULTS: The Baveno VI criteria were cost effective compared with endoscopy in all analyses. For 1000 patients, they produced 0.16 additional QALYs at an incremental cost of £326 ($443.41) over 5 years, resulting in an incremental cost of £2081 ($2830) per additional QALY gained. The incremental net monetary benefit of Baveno VI compared with EGD was £2808 ($3819) over 5 years per patient. Baveno VI criteria also were cost effective in Canada and Spain. Deterministic and probabilistic sensitivity analysis supported these findings. CONCLUSIONS: The findings demonstrate that the Baveno VI criteria are cost effective, suggesting that they should be considered for widespread implementation on the basis of safety, appropriateness, and economic grounds.

acFibroMASH Index for the Diagnosis of Fibrotic MASH and Prediction of Liver-related Events: An International Multicenter Study.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) and fibrotic MASH are significant health challenges. This multi-national study aimed to validate the acMASH index (including serum creatinine and aspartate aminotransferase concentrations) for MASH diagnosis and develop a new index (acFibroMASH) for non-invasively identifying fibrotic MASH and exploring its predictive value for liver-related events (LREs). METHODS: We analyzed data from 3004 individuals with biopsy-proven metabolic dysfunction-associated fatty liver disease (MAFLD) across 29 Chinese and 9 international cohorts to validate the acMASH index and develop the acFibroMASH index. Additionally, we utilized the independent external data from a multi-national cohort of 9034 patients with MAFLD to examine associations between the acFibroMASH index and the risk of LREs. RESULTS: In the pooled global cohort, the acMASH index identified MASH with an area under the receiver operating characteristic curve (AUROC) of 0.802 (95% confidence interval [CI], 0.786-0.818). The acFibroMASH index (including the acMASH index plus liver stiffness measurement) accurately identified fibrotic MASH with an AUROC of 0.808 in the derivation cohort and 0.800 in the validation cohort. Notably, the AUROC for the acFibroMASH index was 0.835 (95% CI, 0.786-0.882), superior to that of the FAST score at 0.750 (95% CI, 0.693-0.800; P < .01) in predicting the 5-year risk of LREs. Patients with acFibroMASH >0.39 had a higher risk of LREs than those with acFibroMASH <0.15 (adjusted hazard ratio, 11.23; 95% CI, 3.98-31.66). CONCLUSIONS: This multi-ethnic study validates the acMASH index as a reliable, noninvasive test for identifying MASH. The newly proposed acFibroMASH index is a reliable test for identifying fibrotic MASH and predicting the risk of LREs.

Severe Cholestasis Predicts Recurrent Primary Sclerosing Cholangitis Following Liver Transplantation.

BACKGROUND AIMS: Primary sclerosing cholangitis (PSC) may reoccur following liver transplantation (LT) and the diagnosis established once imaging studies demonstrate the diagnostic cholangiographic appearance. To evaluate whether the development of recurrent PSC (rPSC) is associated with cholestasis soon after LT, we studied whether changes in hepatic biochemistry within the first 12 months were linked with the development of rPSC and graft loss. METHODS: We conducted a retrospective cohort analysis of 158 transplant recipients with PSC in Canada, and 549 PSC transplant recipients from the United Kingdom. We evaluated serum liver tests within 12 months after LT and the subsequent development of a cholangiographic diagnosis of rPSC as a time-dependent covariate using Cox regression. Severe cholestasis was defined as either alkaline phosphatase> 3xupper limit of normal or total bilirubin> 100 µmol/L. RESULTS: Patients who developed rPSC were more likely to have severe cholestasis versus those without at 3 months (20.5% vs 8.2%, p=0.011), at 6 months (17.9% vs. 10.0%, p=0.026) and 12 months (15.4% vs. 7.8%, p=0.051) in the Canadian cohort and at 12 months in the UK cohort (27.9% vs. 12.6%, p<0.0001). By multivariable analysis, development of severe cholestasis in the Canadian cohort at 3 months (HR=2.41, p=0.046) and in the UK cohort at 12 months (HR=3.141, p<0.0001) were both associated with rPSC. Severe cholestasis at 3 months in the Canadian cohort was predictive of graft loss (HR=3.88, p=0.0001). CONCLUSIONS: The development of cholestasis within 3 to 12 months following LT was predictive of rPSC and graft loss.

Metabolic dysfunction-associated steatohepatitis exhibits sex differences in people with HIV.

OBJECTIVES: People with HIV are at increased risk for metabolic dysfunction-associated steatohepatitis (MASH). Although sex differences are documented in the general population, their role in the context of HIV is less understood. METHODS: This was a multicentre cohort study including people with HIV without viral hepatitis coinfection. A FibroScan-AST (FAST) score >0.35 was used to diagnose MASH with significant liver fibrosis (stage F2-F4). We investigated sex-based differences in MASH trends as a function of age using a segmented linear mixed-effects model. Random effects accounted for clustering by the four sites. Adjusted models included ethnicity, diabetes, hypertension, and detectable HIV viral load. RESULTS: We included 1472 people with HIV (25% women). At baseline, the prevalence of MASH with fibrosis by FAST score was lower in women than in men (4.8% vs. 9.2%, p = 0.008). Based on the adjusted model, male sex (+0.034; p = 0.04), age per year (+0.003; p = 0.05), detectable HIV viral load (+0.034; p = 0.02), and hypertension (+0.03; p = 0.01) were positively associated with MASH with fibrosis. Although men exhibited generally higher FAST scores, FAST scores increased in women during the critical biological age of presumed perimenopause to menopause (between 40 and 50 years), reaching levels similar to those in men by the age of 55 years. CONCLUSION: Despite women with HIV having a lower prevalence of MASH with fibrosis than men, they exhibit an acceleration in FAST score increase around the perimenopausal age. Future studies should target adequate consideration of sex differences in clinical investigation of metabolic dysfunction-associated steatotic liver disease to fill current gaps and implement precision medicine for people with HIV.

Use of non-invasive diagnostic tools for metabolic dysfunction-associated steatohepatitis: A qualitative exploration of challenges and barriers.

BACKGROUND AND AIMS: Non-invasive tests (NITs) are underutilized for diagnosis and risk stratification in metabolic dysfunction-associated steatotic liver disease (MASLD), despite good accuracy. This study aimed to identify challenges and barriers to the use of NITs in clinical practice. METHODS: We conducted a qualitative exploratory study in Germany, Italy, United Kingdom and United States. Phase 1 participants (primary care physicians, hepatologists, diabetologists, researchers, healthcare administrators, payers and patient advocates; n = 29) were interviewed. Phase 2 participants (experts in MASLD; n = 8) took part in a group discussion to validate and expand on Phase 1 findings. Finally, we triangulated perspectives in a hybrid deductive/inductive thematic analysis. RESULTS: Four themes hindering the use of NITs emerged: (1) limited knowledge and awareness; (2) unclear referral pathways for patients affected by liver conditions; (3) uncertainty over the value of NITs in monitoring and managing liver diseases; and (4) challenges justifying system-level reimbursement. Through these themes, participants perceived a stigma associated with liver diseases, and primary care physicians generally lacked awareness, adequate knowledge and skills to use recommended NITs. We identified uncertainties over the results of NITs, specifically to guide lifestyle intervention or to identify patients that should be referred to a specialist. Participants indicated an ongoing need for research and development to improve the prognostic value of NITs and communicating their cost-effectiveness to payers. CONCLUSIONS: This qualitative study suggests that use of NITs for MASLD is limited due to several individual and system-level barriers. Multi-level interventions are likely required to address these barriers.

The role of gut barrier dysfunction in postoperative complications in liver transplantation: pathophysiological and therapeutic considerations.

PURPOSE: Gut barrier dysfunction is a pivotal pathophysiological alteration in cirrhosis and end-stage liver disease, which is further aggravated during and after the operational procedures for liver transplantation (LT). In this review, we analyze the multifactorial disruption of all major levels of defense of the gut barrier (biological, mechanical, and immunological) and correlate with clinical implications. METHODS: A narrative review of the literature was performed using PubMed, PubMed Central and Google from inception until November 29th, 2023. RESULTS: Systemic translocation of indigenous bacteria through this dysfunctional barrier contributes to the early post-LT infectious complications, while endotoxin translocation, through activation of the systemic inflammatory response, is implicated in non-infectious complications including renal dysfunction and graft rejection. Bacterial infections are the main cause of early in-hospital mortality of LT patients and unraveling the pathophysiology of gut barrier failure is of outmost importance. CONCLUSION: A pathophysiology-based approach to prophylactic or therapeutic interventions may lead to enhancement of gut barrier function eliminating its detrimental consequences and leading to better outcomes for LT patients.

Liver fibrosis stage based on the four factors (FIB-4) score or Forns index in adults with chronic hepatitis C.

BACKGROUND: The presence and severity of liver fibrosis are important prognostic variables when evaluating people with chronic hepatitis C (CHC). Although liver biopsy remains the reference standard, non-invasive serological markers, such as the four factors (FIB-4) score and the Forns index, can also be used to stage liver fibrosis. OBJECTIVES: To determine the diagnostic accuracy of the FIB-4 score and Forns index in staging liver fibrosis in people with chronic hepatitis C (CHC) virus, using liver biopsy as the reference standard (primary objective). To compare the diagnostic accuracy of these tests for staging liver fibrosis in people with CHC and explore potential sources of heterogeneity (secondary objectives). SEARCH METHODS: We used standard Cochrane search methods for diagnostic accuracy studies (search date: 13 April 2022). SELECTION CRITERIA: We included diagnostic cross-sectional or case-control studies that evaluated the performance of the FIB-4 score, the Forns index, or both, against liver biopsy, in the assessment of liver fibrosis in participants with CHC. We imposed no language restrictions. We excluded studies in which: participants had causes of liver disease besides CHC; participants had successfully been treated for CHC; or the interval between the index test and liver biopsy exceeded six months. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. We performed meta-analyses using the bivariate model and calculated summary estimates. We evaluated the performance of both tests for three target conditions: significant fibrosis or worse (METAVIR stage ≥ F2); severe fibrosis or worse (METAVIR stage ≥ F3); and cirrhosis (METAVIR stage F4). We restricted the meta-analysis to studies reporting cut-offs in a specified range (+/-0.15 for FIB-4; +/-0.3 for Forns index) around the original validated cut-offs (1.45 and 3.25 for FIB-4; 4.2 and 6.9 for Forns index). We calculated the percentage of people who would receive an indeterminate result (i.e. above the rule-out threshold but below the rule-in threshold) for each index test/cut-off/target condition combination. MAIN RESULTS: We included 84 studies (with a total of 107,583 participants) from 28 countries, published between 2002 and 2021, in the qualitative synthesis. Of the 84 studies, 82 (98%) were cross-sectional diagnostic accuracy studies with cohort-based sampling, and the remaining two (2%) were case-control studies. All studies were conducted in referral centres. Our main meta-analysis included 62 studies (100,605 participants). Overall, two studies (2%) had low risk of bias, 23 studies (27%) had unclear risk of bias, and 59 studies (73%) had high risk of bias. We judged 13 studies (15%) to have applicability concerns regarding participant selection. FIB-4 score The FIB-4 score's low cut-off (1.45) is designed to rule out people with at least severe fibrosis (≥ F3). Thirty-nine study cohorts (86,907 participants) yielded a summary sensitivity of 81.1% (95% confidence interval (CI) 75.6% to 85.6%), specificity of 62.3% (95% CI 57.4% to 66.9%), and negative likelihood ratio (LR-) of 0.30 (95% CI 0.24 to 0.38). The FIB-4 score's high cut-off (3.25) is designed to rule in people with at least severe fibrosis (≥ F3). Twenty-four study cohorts (81,350 participants) yielded a summary sensitivity of 41.4% (95% CI 33.0% to 50.4%), specificity of 92.6% (95% CI 89.5% to 94.9%), and positive likelihood ratio (LR+) of 5.6 (95% CI 4.4 to 7.1). Using the FIB-4 score to assess severe fibrosis and applying both cut-offs together, 30.9% of people would obtain an indeterminate result, requiring further investigations. We report the summary accuracy estimates for the FIB-4 score when used for assessing significant fibrosis (≥ F2) and cirrhosis (F4) in the main review text. Forns index The Forns index's low cut-off (4.2) is designed to rule out people with at least significant fibrosis (≥ F2). Seventeen study cohorts (4354 participants) yielded a summary sensitivity of 84.7% (95% CI 77.9% to 89.7%), specificity of 47.9% (95% CI 38.6% to 57.3%), and LR- of 0.32 (95% CI 0.25 to 0.41). The Forns index's high cut-off (6.9) is designed to rule in people with at least significant fibrosis (≥ F2). Twelve study cohorts (3245 participants) yielded a summary sensitivity of 34.1% (95% CI 26.4% to 42.8%), specificity of 97.3% (95% CI 92.9% to 99.0%), and LR+ of 12.5 (95% CI 5.7 to 27.2). Using the Forns index to assess significant fibrosis and applying both cut-offs together, 44.8% of people would obtain an indeterminate result, requiring further investigations. We report the summary accuracy estimates for the Forns index when used for assessing severe fibrosis (≥ F3) and cirrhosis (F4) in the main text. Comparing FIB-4 to Forns index There were insufficient studies to meta-analyse the performance of the Forns index for diagnosing severe fibrosis and cirrhosis. Therefore, comparisons of the two tests' performance were not possible for these target conditions. For diagnosing significant fibrosis and worse, there were no significant differences in their performance when using the high cut-off. The Forns index performed slightly better than FIB-4 when using the low/rule-out cut-off (relative sensitivity 1.12, 95% CI 1.00 to 1.25; P = 0.0573; relative specificity 0.69, 95% CI 0.57 to 0.84; P = 0.002). AUTHORS' CONCLUSIONS: Both the FIB-4 score and the Forns index may be considered for the initial assessment of people with CHC. The FIB-4 score's low cut-off (1.45) can be used to rule out people with at least severe fibrosis (≥ F3) and cirrhosis (F4). The Forns index's high cut-off (6.9) can be used to diagnose people with at least significant fibrosis (≥ F2). We judged most of the included studies to be at unclear or high risk of bias. The overall quality of the body of evidence was low or very low, and more high-quality studies are needed. Our review only captured data from referral centres. Therefore, when generalising our results to a primary care population, the probability of false positives will likely be higher and false negatives will likely be lower. More research is needed in sub-Saharan Africa, since these tests may be of value in such resource-poor settings.

Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease.

Importance: Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide. It is important to develop noninvasive tests to assess the disease severity and prognosis. Objective: To study the prognostic implications of baseline levels and dynamic changes of the vibration-controlled transient elastography (VCTE)-based scores developed for the diagnosis of advanced fibrosis (Agile 3+) and cirrhosis (Agile 4) in patients with MASLD. Design, Setting, and Participants: This cohort study included data from a natural history cohort of patients with MASLD who underwent VCTE examination at 16 tertiary referral centers in the US, Europe, and Asia from February 2004 to January 2023, of which the data were collected prospectively at 14 centers. Eligible patients were adults aged at least 18 years with hepatic steatosis diagnosed by histologic methods (steatosis in ≥5% of hepatocytes) or imaging studies (ultrasonography, computed tomography or magnetic resonance imaging, or controlled attenuation parameter ≥248 dB/m by VCTE). Main Outcomes and Measures: The primary outcome was liver-related events (LREs), defined as hepatocellular carcinoma or hepatic decompensation (ascites, variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome), liver transplant, and liver-related deaths. The Agile scores were compared with histologic and 8 other noninvasive tests. Results: A total of 16 603 patients underwent VCTE examination at baseline (mean [SD] age, 52.5 [13.7] years; 9600 [57.8%] were male). At a median follow-up of 51.7 (IQR, 25.2-85.2) months, 316 patients (1.9%) developed LREs. Both Agile 3+ and Agile 4 scores classified fewer patients between the low and high cutoffs than most fibrosis scores and achieved the highest discriminatory power in predicting LREs (integrated area under the time-dependent receiver-operating characteristic curve, 0.89). A total of 10 920 patients (65.8%) had repeated VCTE examination at a median interval of 15 (IQR, 11.3-27.7) months and were included in the serial analysis. A total of 81.9% of patients (7208 of 8810) had stable Agile 3+ scores and 92.6% of patients (8163 of 8810) had stable Agile 4 scores (same risk categories at both assessments). The incidence of LREs was 0.6 per 1000 person-years in patients with persistently low Agile 3+ scores and 30.1 per 1000 person-years in patients with persistently high Agile 3+ scores. In patients with high Agile 3+ score at baseline, a decrease in the score by more than 20% was associated with substantial reduction in the risk of LREs. A similar trend was observed for the Agile 4 score, although it missed more LREs in the low-risk group. Conclusions and Relevance: Findings of this study suggest that single or serial Agile scores are highly accurate in predicting LREs in patients with MASLD, making them suitable alternatives to liver biopsy in routine clinical practice and in phase 2b and 3 clinical trials for steatohepatitis.

Fibroscan-Aspartate Aminotransferase Score Predicts Liver-Related Outcomes, but Not Extrahepatic Events, in a Multicenter Cohort of People With Human Immunodeficiency Virus.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is frequent in people with human immunodeficiency virus (PWH). The Fibroscan-aspartate aminotransferase (FAST) score was developed to identify patients with nonalcoholic steatohepatitis (NASH) and significant fibrosis. We investigated prevalence of NASH with fibrosis and the value of FAST score in predicting clinical outcomes in PWH. METHODS: Transient elastography (Fibroscan) was performed in PWH without viral hepatitis coinfection from 4 prospective cohorts. We used FAST >0.35 to diagnose NASH with fibrosis. Incidence and predictors of liver-related outcomes (hepatic decompensation, hepatocellular carcinoma) and extrahepatic events (cancer, cardiovascular disease) were evaluated through survival analysis. RESULTS: Of the 1472 PWH included, 8% had FAST >0.35. Higher body mass index (adjusted odds ratio [aOR], 1.21 [95% confidence interval {CI}, 1.14-1.29]), hypertension (aOR, 2.24 [95% CI, 1.16-4.34]), longer time since HIV diagnosis (aOR, 1.82 [95% CI, 1.20-2.76]), and detectable HIV RNA (aOR, 2.22 [95% CI, 1.02-4.85]) were associated with FAST >0.35. A total of 882 patients were followed for a median of 3.8 years (interquartile range, 2.5-4.2 years). Overall, 2.9% and 11.1% developed liver-related and extrahepatic outcomes, respectively. Incidence of liver-related outcomes was higher in patients with FAST >0.35 versus FAST ≤0.35 (45.1 [95% CI, 26.2-77.7] vs 5.0 [95% CI, 2.9-8.6] per 1000 person-years). FAST >0.35 remained an independent predictor of liver-related outcomes (adjusted hazard ratio, 4.97 [95% CI, 1.97-12.51]). Conversely, FAST did not predict extrahepatic events. CONCLUSIONS: A significant proportion of PWH may have NASH with significant liver fibrosis. FAST score predicts liver-related outcomes and can help management of this high-risk population.

Evaluation of recipients with significant comorbidity - Patients with cardiovascular disease.

Liver transplant(ation) (LT) is the most effective treatment for patients with decompensated liver disease. The increasing prevalence of obesity and type 2 diabetes and the growing number of patients with non-alcoholic fatty liver disease being evaluated for LT, have resulted in a greater proportion of LT candidates presenting with a higher risk of cardiovascular disease. As cardiovascular disease is a major cause of morbidity and mortality after LT, a thorough cardiovascular evaluation pre-LT is crucial. In this review, we discuss the latest evidence on the cardiovascular evaluation of LT candidates and we focus on the most prevalent conditions, namely ischaemic heart disease, atrial fibrillation and other arrhythmias, valvular heart disease, and cardiomyopathies. LT candidates undergo an electrocardiogram, a resting transthoracic echocardiography and an assessment of their cardiopulmonary functional ability as part of their standardised pre-LT work-up. Further diagnostic work-up is undertaken based on the results of the baseline evaluation and may include a coronary computed tomography angiography in patients with cardiovascular risk factors. The evaluation of potential LT candidates for cardiovascular disease requires a multidisciplinary approach, with input from anaesthetists, cardiologists, hepatologists and transplant surgeons.

A global research priority agenda to advance public health responses to fatty liver disease.

BACKGROUND & AIMS: An estimated 38% of adults worldwide have non-alcoholic fatty liver disease (NAFLD). From individual impacts to widespread public health and economic consequences, the implications of this disease are profound. This study aimed to develop an aligned, prioritised fatty liver disease research agenda for the global health community. METHODS: Nine co-chairs drafted initial research priorities, subsequently reviewed by 40 core authors and debated during a three-day in-person meeting. Following a Delphi methodology, over two rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the priorities, via Qualtrics XM, indicating agreement using a four-point Likert-scale and providing written feedback. The core group revised the draft priorities between rounds. In R2, panellists also ranked the priorities within six domains: epidemiology, models of care, treatment and care, education and awareness, patient and community perspectives, and leadership and public health policy. RESULTS: The consensus-built fatty liver disease research agenda encompasses 28 priorities. The mean percentage of 'agree' responses increased from 78.3 in R1 to 81.1 in R2. Five priorities received unanimous combined agreement ('agree' + 'somewhat agree'); the remaining 23 priorities had >90% combined agreement. While all but one of the priorities exhibited at least a super-majority of agreement (>66.7% 'agree'), 13 priorities had <80% 'agree', with greater reliance on 'somewhat agree' to achieve >90% combined agreement. CONCLUSIONS: Adopting this multidisciplinary consensus-built research priorities agenda can deliver a step-change in addressing fatty liver disease, mitigating against its individual and societal harms and proactively altering its natural history through prevention, identification, treatment, and care. This agenda should catalyse the global health community's efforts to advance and accelerate responses to this widespread and fast-growing public health threat. IMPACT AND IMPLICATIONS: An estimated 38% of adults and 13% of children and adolescents worldwide have fatty liver disease, making it the most prevalent liver disease in history. Despite substantial scientific progress in the past three decades, the burden continues to grow, with an urgent need to advance understanding of how to prevent, manage, and treat the disease. Through a global consensus process, a multidisciplinary group agreed on 28 research priorities covering a broad range of themes, from disease burden, treatment, and health system responses to awareness and policy. The findings have relevance for clinical and non-clinical researchers as well as funders working on fatty liver disease and non-communicable diseases more broadly, setting out a prioritised, ranked research agenda for turning the tide on this fast-growing public health threat.

Systematic Review and Meta-analysis: The Role of Diet in the Development of Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: The association of nonalcoholic fatty liver disease (NAFLD) with dietary factors is well established but not thoroughly investigated. This systematic review and meta-analysis synthesizes available evidence regarding the effect of nutrition on the presence and severity of NAFLD. METHODS: A literature search was conducted identifying studies published between January 1985 and May 2021. We included studies with a dietary assessment and anthropometry based on validated tools, performed by a qualified dietitian or a trained health professional. We examined differences between patients with NAFLD and healthy controls as well as patients with NAFLD and nonalcoholic steatohepatitis (NASH). Risk of bias was assessed with the Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I) tool. RESULTS: There were 60 eligible studies with 100,621 patients. The risk of bias was moderate for the majority of studies (41/60; 68%). According to meta-analyses, total caloric intake was higher in patients with NAFLD compared with controls (mean difference, 78.08; 95% confidence interval, 41.03-115.13). Macronutrient (protein, fat, and carbohydrate) consumption as proportion of total caloric intake and daily intake of fiber, caffeine and vitamins E, A, and C did not significantly differ between patients with NAFLD and controls. Soft drink consumption had a trend towards association with the presence of NAFLD. However, the odds ratio was 4.4 and the confidence intervals very wide. Finally, there was no significant difference in any comparison between patients with NAFLD and NASH, although the number of patients was relatively small. All meta-analyses had significant heterogeneity. CONCLUSIONS: Overall, despite high heterogeneity among studies, this meta-analysis demonstrated that higher caloric intake is positively associated with NAFLD, whereas diet composition in macronutrients was not associated with the presence or severity of the disease.

Health-related Quality of Life in Patients With Nonalcoholic Fatty Liver Disease: A Prospective Multi-center UK Study.

BACKGROUND & AIMS: It is unclear whether health-related quality of life (HRQoL) is impaired in patients with nonalcoholic fatty liver disease (NAFLD) without advanced fibrosis and how this compares with the general population. We aimed to assess HRQoL in patients with NAFLD in comparison to the general population and any associations of fibrosis severity and metabolic comorbidities with impairments in HRQoL. METHODS: We prospectively enrolled 513 consecutive patients with NAFLD who completed the EuroQol 5-dimensional questionnaire (EQ-5D) and Chronic Liver Disease Questionnaires (CLDQ). Demographic and clinical information, liver biopsy results, and/or liver stiffness (LS) by transient elastography were recorded. A general population sub-cohort of the Health Survey for England 2018 was used as a comparator (n = 5483), and a 1:1 propensity-score (PS) matching was performed, according to age, sex, body mass index, and type 2 diabetes mellitus (T2DM). RESULTS: EQ-5D-5L utility was significantly lower in 466 PS-matched patients with NAFLD compared with PS-matched controls (0.77 ± 0.27 vs 0.84 ± 0.19; P < .001), even in those without advanced fibrosis (F ≤2 or LS <8kPa) (0.80 ± 0.24 vs 0.84 ± 0.19; P = .024). HRQoL measures (EQ-5D-5L, EQ-VAS, CLDQ) did not differ between patients with NAFLD with and without advanced fibrosis. LS was independently associated with lower EQ-5D-5L in all patients with NAFLD but not in those without advanced fibrosis. In the latter, lower EQ-5D-5L was associated with female sex, T2DM, and depression. CONCLUSIONS: Patients with NAFLD, even those without advanced fibrosis, have worse HRQoL compared with the general population. In patients with NAFLD without advanced fibrosis, HRQoL is independently associated with non-liver comorbidities but not LS. Multi-disciplinary management is therefore required in NAFLD, irrespective of fibrosis severity.

Bacterascites confers poor patient prognosis beyond MELD prediction.

Spontaneous bacterial peritonitis (SBP) is a well-recognized clinical entity with a poor prognosis. In comparison, the prevalence, microbiological flora, and prognostic significance of bacterascites (BA) (the presence of organism on culture but ascitic PMN <250 cells/mm³) is largely unknown. We, therefore, assessed the prognosis and predictors of outcome in patients with BA in comparison with those with SBP. Ascitic fluid cultures from consecutive patients with cirrhosis from 2008 to 2018 were reviewed retrospectively, and patients with SBP and BA were identified. Baseline demographic, laboratory, and microbiological data were collated and analyzed as prognostic indicators, and clinical outcomes were recorded. Patients were censored at the time of LT, death, or last follow-up. For this study 176 and 213 cases of SBP and BA, respectively, were identified and included. Patients with SBP had significantly higher Model for End-Stage Liver Disease (MELD) ( p =<0.01), peripheral blood WCC ( p < 0.01), and higher rates of Enterobacteriaceae ( p < 0.01) and multi-drug resistant pathogens ( p < 0.01). Survival at 1 and 3 months was lower in patients with SBP ( p < 0.01) when compared with BA but at 6 months and beyond, no significant difference remained. After the exclusion of deaths within 30 days of presentation, survival between SBP and BA was equivocal at all time points. Mortality was substantially higher across all MELD groupings for both SBP and BA when compared with the predicted mortality calculated by the MELD score alone. BA has a negative impact on patient survival above that predicted by the MELD score. It has similar impact to SBP on patient survival beyond 1 month suggesting it should be seen as a poor prognostic marker and prompt consideration of LT where appropriate. Further studies evaluating the role of secondary prophylaxis in this group are required.

Population screening for liver fibrosis: Toward early diagnosis and intervention for chronic liver diseases.

Cirrhosis, highly prevalent worldwide, develops after years of hepatic inflammation triggering progressive fibrosis. Currently, the main etiologies of cirrhosis are non-alcoholic fatty liver disease and alcohol-related liver disease, although chronic hepatitis B and C infections are still major etiological factors in some areas of the world. Recent studies have shown that liver fibrosis can be assessed with relatively high accuracy noninvasively by serological tests, transient elastography, and radiological methods. These modalities may be utilized for screening for liver fibrosis in at-risk populations. Thus far, a limited number of population-based studies using noninvasive tests in different areas of the world indicate that a significant percentage of subjects without known liver disease (around 5% in general populations and a higher rate -18% to 27%-in populations with risk factors for liver disease) have significant undetected liver fibrosis or established cirrhosis. Larger international studies are required to show the harms and benefits before concluding that screening for liver fibrosis should be applied to populations at risk for chronic liver diseases. Screening for liver fibrosis has the potential for changing the current approach from diagnosing chronic liver diseases late when patients have already developed complications of cirrhosis to diagnosing liver fibrosis in asymptomatic subjects providing the opportunity of preventing disease progression.