Persons with metabolic dysfunction-associated steatotic liver disease are at increased risk of severe depression.

BACKGROUND AND AIM: Few population-based studies have investigated the association between metabolic dysfunction-associated steatotic liver disease (MASLD) and depression. Additionally, it remains unclear if depression affects progression to major adverse liver outcomes (MALO) in MASLD. METHODS: All patients in Sweden with newly diagnosed MASLD between 2006 and 2020 were identified from the National Patient Register. Each patient was matched on age, sex, inclusion year, and municipality with up to 10 comparators from the general population. Cox regression was used to compare rates of severe depression in persons with MASLD to the comparators. In persons with MASLD, Cox regression was used to estimate rates of MALO using severe depression before baseline or diagnosed during follow-up as a time-varying exposure. RESULTS: We included 11 301 persons with MASLD and 104 205 comparators who were followed for a median of 3.9 (IQR 1.5-7.6) and 4.9 years (IQR 2.3-8.7), respectively. The median age was 56 years and 5576 of 11 301 (49.3%) persons with MASLD were male. Incident severe depression developed in 228 of 11 301 (2.0%) persons with MASLD and 1160 of 104 205 (1.1%) comparators (fully adjusted hazard ratio [HR] = 1.8, 95% CI = 1.5-2.1). Of persons with MASLD, 25 of 1229 (2.0%) of those with severe depression before or after baseline progressed to MALO compared to 322 of 10 326 (3.1%) of those without severe depression (fully adjusted HR = 1.0, 95% CI = .6-1.5). CONCLUSIONS: We confirm an association between MASLD and severe depression. However, no association between severe depression and incident MALO was found, but conclusions are limited by few observed outcomes.

Risk of major adverse liver outcomes among first-degree relatives of individuals with MASLD.

BACKGROUND & AIMS: Previous studies have suggested an increased risk of major adverse liver outcomes (MALO) in relatives of patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, granular and longitudinal evidence is lacking on the future risk of MALO among family members of individuals with MASLD. METHODS: We identified 3526 first-degree relatives (FDRs) and 11 079 general population comparators to 1328 patients with MASLD diagnosed between 1974 and 2021, with detailed clinical data, including liver histology in 71% of patients. MALO was defined through diagnostic coding for cirrhosis or its complications. Cox regression models were used to estimate adjusted hazard ratios (aHRs) for MALO among FDRs compared to general population comparators. Cumulative incidence accounting for competing risks was calculated. RESULTS: During a median follow-up of 13.4 years, there were 65 (2%, 1.12/1000 person-years) and 225 (2%, 1.26/1000 person-years) MALO events in FDRs and general population comparators respectively. After adjusting for demographic factors and comorbidities, FDRs were at no increased risk of MALO (aHR = 0.99, 95% CI: 0.74-1.33). Increased relative rates of MALOs were, however, observed in some subgroups, including parents, although absolute risk estimates were low and comparable to the general population. CONCLUSIONS: FDRs of patients with MASLD did not have a higher rate of incident MALO than the general population. Since the absolute risk of MALO in relatives of patients with MASLD was low, these results do not support systematic screening of MASLD-related fibrosis in relatives of patients with MASLD.

MRI-AST (MAST) Score Accurately Predicts Major Adverse Liver Outcome, Hepatocellular Carcinoma, Liver Transplant, and Liver-Related Death.

BACKGROUND & AIMS: The MRI-AST (MAST) score accurately identifies patients with at-risk nonalcoholic steatohepatitis, defined as nonalcoholic steatohepatitis with nonalcoholic fatty liver disease activity score ≥4 and fibrosis stage ≥2 at highest risk for disease progression. It is important to determine the robustness of the MAST score in predicting major adverse liver outcomes (MALO), hepatocellular carcinoma (HCC), liver transplant, and death. METHODS: This retrospective analysis included patients with nonalcoholic fatty liver disease from a tertiary care center who underwent magnetic resonance imaging proton density fat fraction, magnetic resonance elastography, and laboratory testing within 6 months from 2013 to 2022. Other causes of chronic liver disease were excluded. Hazard ratios between logit MAST and MALO (ascites, hepatic encephalopathy, or bleeding esophageal varices), liver transplant, HCC, or liver-related death were computed using a Cox proportional hazards regression model. We computed the hazard ratio of MALO or death associated with MAST scores 0.165-0.242 and 0.242-1.000, using MAST scores 0.000-0.165 as the reference group. RESULTS: Among 346 total patients, average age was 58.8 years with 52.9% females and 34.4% with type 2 diabetes. Average alanine aminotransferase was 50.7 IU/L (24.3-60.0 IU/L), aspartate aminotransferase was 38.05 IU/L (22.00-41.00 IU/L), platelets were 242.9 × 109/L (193.8-290.0 × 109/L), proton density fat fraction was 12.90% (5.90%-18.22%), and liver stiffness on magnetic resonance elastography was 2.75 kPa (2.07-2.90 kPa). Median follow-up was 29.5 months. Fourteen had adverse outcomes, including 10 MALO, 1 HCC, 1 liver transplant, and 2 liver-related deaths. The Cox regression of MAST versus adverse event rate had a hazard ratio of 2.01 (95% confidence interval, 1.59-2.54; P < .0001) for each 1 logit unit increases in MAST. The corresponding Harrell concordance statistic (C statistic) was 0.919 (95% confidence interval, 0.865-0.953). The MAST score ranges of 0.165-0.242 and 0.242-1.0, respectively, had adverse event rate hazard ratio of 7.75 (1.40-42.9; P = .0189) and 22.11 (6.59-74.2; P < .0000) relative to MAST 0-0.165. CONCLUSIONS: The MAST score noninvasively identifies at-risk nonalcoholic steatohepatitis and accurately predicts MALO, HCC, liver transplant, and liver-related death.

Impacts of glucagon-like peptide-1 receptor agonists on the risk of adverse liver outcomes in patients with metabolic dysfunction-associated steatotic liver disease cirrhosis and type 2 diabetes.

BACKGROUND/AIMS: We examined the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) initiation on long-term Adverse Liver Outcomes (ALO) in patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) cirrhosis and type 2 diabetes using real-world data from the MarketScan database. METHODS: We conducted a retrospective cohort study of patients with MASLD cirrhosis and type 2 diabetes between 2012 and 2020. Cox proportional hazard models examine the association between GLP-1RAs initiation, modelled as time-dependent, and the risk of ALO, a composite endpoint defined by the first occurrence of hepatic decompensation(s), portal hypertension, hepatocellular carcinoma (HCC) or liver transplantation (LT). We used Overlap Propensity Score Weighting (OPSW) to account for confounding. The study included 459 GLP-1RAs and 4837 non-GLP-1RAs patients. RESULTS: The non-GLP-1RAs patients presented with 1411 (29%) ALO over 7431.7 person years, while GLP-1RAs patients had 32 (7%) ALO over 586.6 person years - risk rate difference 13.5 (95% CI: 11.4-15.7) per 100 person-years. The OPSW-adjusted risk of ALO was reduced by 36% (hazard ratio [HR]: 0.64; 95% CI: 0.54-0.76) in patients with vs. without GLP-1RAs initiation. GLP-1RAs initiation was associated with significant reductions in the adjusted risk of hepatic decompensation (HR: 0.74; 95% CI: 0.61-0.88), portal hypertension (HR: 0.73; 95% CI: 0.60-0.88), HCC (HR: 0.37; 95% CI: 0.20-0.63) and LT (HR: 0.24; 95% CI: 0.12-0.43). CONCLUSION: The use of GLP-1RAs was associated with significant risk reductions in long-term adverse liver outcomes, including hepatic decompensation, portal hypertension, HCC and LT, in MASLD cirrhosis patients with type 2 diabetes.

Long-term major adverse liver outcomes in 1,260 patients with non-cirrhotic NAFLD.

Background & Aims: Long-term studies of the prognosis of NAFLD are scarce. Here, we investigated the risk of major adverse liver outcomes (MALO) in a large cohort of patients with NAFLD. Methods: We conducted a cohort study with data from Swedish university hospitals. Patients (n = 1,260) with NAFLD without cirrhosis were diagnosed through biopsy or radiology, and had fibrosis estimated through vibration-controlled transient elastography, biopsy, or FIB-4 score between 1974 and 2020 and followed up through 2020. Each patient was matched on age, sex, and municipality with up to 10 reference individuals from the general population (n = 12,529). MALO were ascertained from Swedish national registers. The rate of events was estimated by Cox regression. Results: MALO occurred in 111 (8.8%, incidence rate = 5.9/1,000 person-years) patients with NAFLD and 197 (1.6%, incidence rate = 1.0/1,000 person-years) reference individuals during a median follow up of 13 years. The rate of MALO was higher in patients with NAFLD (hazard ratio = 6.6; 95% CI = 5.2-8.5). The risk of MALO was highly associated with the stage of fibrosis at diagnosis. In the biopsy subcohort (72% of total sample), there was no difference in risk between patients with and without non-alcoholic steatohepatitis. The 20-year cumulative incidences of MALO were 2% for the reference population, 3% for patients with F0, and 35% for F3. Prognostic information from biopsy was comparable to FIB-4 (C-indices around 0.73 vs. 0.72 at 10 years). Conclusions: This study provides updated information on the natural history of NAFLD, showing a high rate of progression to cirrhosis in F3 and a similar prognostic capacity of non-invasive tests to liver biopsy. Impact and implications: Several implications for clinical care and future research may be noted based on these results. First, the risk estimates for cirrhosis development are important when communicating risk to patients and deciding on clinical monitoring and treatment. Estimates can also be used in updated health-economic evaluations, and for regulatory agencies. Second, our results again highlight the low predictive information obtained from ascertaining NASHstatus by histology and call for more objective means by which to define NASH. Such methods may include artificial intelligence-supported digital pathology. We highlight that NASH is most likely the causal factor for fibrosis progression in NAFLD, but the subjective definition makes the prognostic value of a histological NASH diagnosis of limited value. Third, the finding that prognostic information from biopsy and the very simple Fibrosis-4 score were comparable is important as it may lead to fewer biopsies and further move the field towards non-invasive means by which to define fibrosis and, importantly, use non-invasive tests as outcomes in clinical trials. However, all modalities had modest discriminatory capacity and new risk stratification systems are needed in NAFLD. Repeated measures of non-invasive scores may be a potential solution.

Impacts of bariatric surgery on adverse liver outcomes: a systematic review and meta-analysis.

BACKGROUND: Bariatric surgery has been reported to improve degeneration, inflammation, and fibrosis in nonalcoholic fatty liver disease, but the effects of bariatric surgery on the associated clinical outcomes is not known. OBJECTIVES: This work aimed to assess the impacts of bariatric surgery on adverse liver outcomes in people with obesity. SETTING: An electronic search was performed on EMBASE, PubMed, and Cochrane Central Register of Controlled Trials (CENTRAL). METHODS: The primary outcome was the incidence of adverse liver outcomes following bariatric surgery. Liver cancer, cirrhosis, liver transplantation, liver failure, and liver-related mortality were defined as adverse hepatic outcomes. RESULTS: We analyzed data from 18 studies comprising 16,800,287 post bariatric surgical patients and 10,595,752 control patients. We found that bariatric surgery reduced the risk of adverse liver outcomes in people with obesity (hazard ratio [HR] = .33, 95% confidence interval [CI] = .31-.34; I2 = 98.1%). The subgroup analysis showed that bariatric surgery reduced the risk of nonalcoholic cirrhosis (HR = .07, 95% CI = .06-.08; I2 = 99.3%) and liver cancer (HR = .37, 95% CI = .35-.39; I2 = 97.8%), although bariatric surgery may also increase the risk of postoperative alcoholic cirrhosis (HR = 1.32, 95% CI = 1.35-1.59). CONCLUSIONS: This systematic review and meta-analysis revealed that bariatric surgery lowered the incidence of adverse hepatic outcomes. However, bariatric surgery may also increase the risk of alcoholic cirrhosis after surgery. Future randomized controlled trials are required to further investigate the effects of bariatric surgery on liver of people with obesity.

Impact of the COVID-19 pandemic on the care and outcomes of people with NAFLD-related cirrhosis.

Background & Aims: The COVID-19 pandemic has had a major negative impact on health systems and many chronic diseases globally. We aimed to evaluate the impact of the first year of the pandemic on the outcomes of people with NAFLD cirrhosis. Methods: We conducted a before-after study in four University hospitals in Catalonia, Spain. Study subperiods were divided into Pre-pandemic (March/2019-February/2020) vs. Pandemic (March/2020-February/2021). The primary outcome was the rate of first liver-related event (LRE). Overall clinical outcomes (LREs plus cardiovascular plus all-cause mortality) were also assessed. Results: A total of 354 patients were included, all of whom were compensated at the beginning of the study period; 83 individuals (23.5%) had a history of prior hepatic decompensation. Mean age was 67.3 years and 48.3% were female. Median BMI was 31.2 kg/m2 and type 2 diabetes was present in 72.8% of patients. The rates of first LRE in the Pre-pandemic and Pandemic periods were 7.4% and 11.3% (p = 0.12), respectively. Whilst the rate of overall events was significantly higher in the Pandemic period (9.9% vs. 17.8%; p = 0.009), this was strongly associated with COVID-19-related deaths. The rate of worsened metabolic status was significantly higher in the Pandemic period (38.4% vs. 46.1%; p = 0.041), yet this was not associated with the risk of first LRE during the Pandemic period, whereas type 2 diabetes (odds ratio [OR] 3.77; 95% CI 1.15-12.32; p = 0.028), albumin <4 g/L (OR 4.43; 95% CI 1.76-11.17; p = 0.002) and Fibrosis-4 score >2.67 (OR 15.74; 95% CI 2.01-123.22; p = 0.009) were identified as risk factors in the multivariable analysis. Conclusion: Overall, people with NAFLD cirrhosis did not present poorer liver-related outcomes during the first year of the pandemic. Health system preparedness seems key to ensure that people with NAFLD cirrhosis receive appropriate care during health crises. Lay summary: Mobility restrictions and social stress induced by the COVID-19 pandemic have led to increased alcohol drinking and worsened metabolic control (e.g., weight gain, poor control of diabetes) in a large proportion of the population in many countries. We aimed to analyze whether people with cirrhosis due to non-alcoholic fatty liver disease, who are particularly vulnerable to such lifestyle modifications, were significantly impacted during the first year of the pandemic. We compared the clinical situation of 354 patients one year before the pandemic and one year after. We found that although metabolic control was indeed worse after the first year of the pandemic and patients presented worse clinical outcomes, the latter was mostly due to non-liver causes, namely COVID-19 itself. Moreover, the care provided to these patients did not worsen during the first year of the pandemic.