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Background: Prior studies suggest a link between metabolic dysfunction-associated steatotic liver disease (MASLD) and incident arrhythmias, including atrial fibrillation (AF). However, robust data are lacking from cohorts with liver histology, which remains the gold standard for staging MASLD severity., Methods: This population-based cohort included all Swedish adults with histologically-confirmed MASLD and without prior cardiac arrhythmias (1966-2016; n = 11,206). MASLD was defined from prospectively-recorded histopathology, and characterized as simple steatosis, non-fibrotic steatohepatitis (MASH), non-cirrhotic fibrosis, or cirrhosis. MASLD patients were matched to ≤ 5 controls without MASLD or arrhythmias, by age, sex, calendar year and county (n = 51,856). Using Cox proportional hazards modeling, we calculated multivariable-adjusted hazard ratios (aHRs) for incident arrhythmias (including AF, bradyarrhythmias, other supraventricular arrhythmias, ventricular arrhythmias/cardiac arrest)., Results: Over a median follow-up of 10.8 years, incident arrhythmias were confirmed in 1351 MASLD patients (10.3/1000 person-years [PY]) and 6493 controls (8.7/1000PY; difference = 1.7/1000PY; aHR = 1.30, 95%CI 1.22-1.38), and MASLD patients had significantly higher rates of incident AF (difference = 0.9/1000PY; aHR = 1.26, 95%CI 1.18-1.35). Rates of both overall arrhythmias and AF were significantly elevated across all MASLD histological groups, particularly cirrhosis (differences, 8.5/1000PY and 5.3/1000PY, respectively). In secondary analyses, MASLD patients also had significantly higher rates of incident ventricular arrhythmias/cardiac arrest (aHR = 1.53, 95%CI 1.30-1.80), bradyarrhythmias (aHR = 1.26, 95%CI 1.06-1.48), and other supraventricular arrhythmias (aHR = 1.27, 95%CI 1.00-1.62), compared to controls., Conclusions: Compared to matched controls, patients with biopsy-confirmed MASLD had modest but significantly higher incidence of cardiac arrhythmias, including AF, bradyarrhythmias, other supraventricular arrhythmias and ventricular arrhythmias/cardiac arrest. Excess risk was observed across all stages of MASLD and was highest with cirrhosis., (© 2023. The Author(s).)

More data are needed regarding the long-term impact of the histological progression of non-alcoholic fatty liver disease (NAFLD) on long-term outcomes, including end-stage liver disease (ESLD) and mortality. We included Swedish adults with biopsy-confirmed non-cirrhotic NAFLD and ≥2 liver biopsies >6 months apart (1969-2017; n = 718). NAFLD was categorized at initial biopsy as simple steatosis, non-fibrotic steatohepatitis (NASH), or non-cirrhotic fibrosis. NAFLD progression was defined by histological changes between biopsies (i.e. incident NASH, incident fibrosis, fibrosis progression, cirrhosis). Using Cox regression, we estimated multivariable adjusted hazard ratios (aHRs) and 95% CIs for incident ESLD (i.e. hospitalization for decompensated cirrhosis, hepatocellular carcinoma or liver transplantation) and mortality, according to NAFLD progression vs. stable/regressed disease. At initial biopsy, 497 patients (69.2%) had simple steatosis, 90 (12.5%) had non-fibrotic NASH, and 131 (18.2%) had non-cirrhotic fibrosis. Over a median of 3.4 years between biopsies, 30.4% (218/718) experienced NAFLD progression, including 12.5% (62/497) with incident non-fibrotic NASH, 24.0% (141/587) with incident fibrosis, and 5.6% (40/718) with cirrhosis. Compared to stable/regressed disease, NAFLD progression was associated with significantly higher rates of developing incident ESLD (23.8 vs. 11.4/1,000 person-years [PY]; difference = 12.4/1,000 PY; aHR 1.65, 95% CI 1.17-2.32). While the highest ESLD incidence occurred with progression to cirrhosis (difference vs. stable/regressed disease = 56.3/1,000 PY), significant excess risk was also found with earlier transitions, including from simple steatosis to incident fibrosis (difference vs. stable/regressed disease = 18.9/1,000 PY). In contrast, all-cause mortality rates did not appear to differ when NAFLD progression was compared to stable/regressed disease (difference = 4.7/1,000 PY; aHR 0.99, 95% CI 0.78-1.24). In a nationwide, real-world cohort of patients with paired NAFLD biopsies, histological disease progression contributed to significantly higher rates of developing incident ESLD, but did not appear to impact all-cause mortality. Currently, data are scarce regarding the long-term impact of histological progression or regression of non-alcoholic fatty liver disease (NAFLD) on subsequent risk of adverse clinical outcomes, including the development of end-stage liver disease and mortality. This is particularly important because randomized-controlled trials of NAFLD therapeutics currently focus on short-term histological endpoints as presumed surrogates for those major clinical outcomes. Thus, the results from this study can help inform the optimal design of future NAFLD therapeutic trials, while also providing the necessary evidence base for public health policies focused on preventing the development and progression of NAFLD. [Display omitted] • In adults with NAFLD and paired clinical liver biopsies, a substantial proportion experienced progression between biopsies. • NAFLD progression was associated with a markedly higher incidence of end-stage liver disease. • In contrast, NAFLD progression was not associated with significantly worse overall mortality. [ABSTRACT FROM AUTHOR]

Background and Aims: Antibiotics affect the gut microbiome. Preclinical studies suggest a role of gut dysbiosis in the development of nonalcoholic fatty liver disease (NAFLD), but data from large cohorts with liver histology are lacking. Methods: In this nationwide case–control study, Swedish adults with histologically confirmed early‐stage NAFLD (total n = 2584; simple steatosis n = 1435; steatohepatitis (NASH) n = 383; non‐cirrhotic fibrosis n = 766) diagnosed January 2007–April 2017 were included and matched to ≤5 population controls (n = 12 646) for age, sex, calendar year and county of residence. Data for cumulative antibiotic dispensations and defined daily doses were accrued until 1 year before the matching date. Using conditional logistic regression, multivariable‐adjusted odds ratios (aORs) were calculated. In a secondary analysis, NAFLD patients were compared with their full siblings (n = 2837). Results: Previous antibiotic use was seen in 1748 (68%) NAFLD patients versus 7001 (55%) controls, corresponding to 1.35‐fold increased odds of NAFLD (95% CI = 1.21–1.51) in a dose‐dependent manner (pfor trend <.001). Estimates were comparable for all histologic stages (p >.05). The highest risk of NAFLD was observed after treatment with fluoroquinolones (aOR 1.38; 95% CI = 1.17–1.59). Associations remained robust when patients were compared with their full siblings (aOR 1.29; 95% CI = 1.08–1.55). Antibiotic treatment was only linked to NAFLD in patients without metabolic syndrome (aOR 1.63; 95% CI = 1.35–1.91) but not in those with metabolic syndrome (aOR 1.09; 95% CI = 0.88–1.30). Conclusions: Antibiotic use may be a risk factor for incident NAFLD, especially in individuals without the metabolic syndrome. The risk was highest for fluoroquinolones and remained robust in sibling comparisons with whom individuals share genetic and early environmental susceptibilities. [ABSTRACT FROM AUTHOR]

Background and Aims: Some, but not all, prior studies have suggested that patients with chronic liver disease are at increased risk of contracting COVID-19 and developing more severe disease. However, nationwide data are lacking from well-phenotyped cohorts with liver histology and comparisons to matched general population controls.Methods: We conducted a nationwide cohort study of all Swedish adults with chronic liver disease (CLD) confirmed by liver biopsy between 1966 and 2017 (n = 42,320), who were alive on February 1, 2020. CLD cases were matched to ≤ 5 population comparators by age, sex, calendar year and county (n = 182,147). Using Cox regression, we estimated multivariable-adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for COVID-19 hospitalization and severe COVID-19 (intensive care admission or death due to COVID-19).Results: Between February 1 and July 31, 2020, 161 (0.38%) CLD patients and 435 (0.24%) general population controls were hospitalized with COVID-19 (aHR = 1.36, 95% CI = 1.11-1.66), while 65 (0.15%) CLD patients and 191 (0.10%) controls developed severe COVID-19 (aHR = 1.08, 95% CI = 0.79-1.48). Results were similar in patients with CLD due to alcohol use, nonalcoholic fatty liver disease, viral hepatitis, autoimmune hepatitis, and other etiologies. Among patients with cirrhosis (n = 2549), the aHRs for COVID-19 hospitalization and for severe COVID-19 were 1.08 (95% CI 0.48-2.40) and 1.23 (95% CI = 0.37-4.04), respectively, compared to controls. Moreover, among all patients diagnosed with COVID-19, the presence of underlying CLD was not associated with increased mortality (aHR = 0.85, 95% CI = 0.61-1.19).Conclusions: In this nationwide cohort, patients with CLD had a higher risk of hospitalization for COVID-19 compared to the general population, but they did not have an increased risk of developing severe COVID-19. [ABSTRACT FROM AUTHOR]

Longitudinal data are scarce regarding the natural history and long-term risk of mortality in children and young adults with biopsy-confirmed non-alcoholic fatty liver disease (NAFLD). This nationwide, matched cohort study included all Swedish children and young adults (≤25 years) with biopsy-confirmed NAFLD (1966–2017; n = 718). NAFLD was confirmed histologically from all liver biopsies submitted to Sweden's 28 pathology departments, and further categorized as simple steatosis or steatohepatitis (NASH). Patients with NAFLD were matched to ≤5 general population controls by age, sex, calendar year and county (n = 3,457). To account for shared genetic and early-life factors, we also matched patients with NAFLD to full-sibling comparators. Using Cox regression, we estimated multivariable-adjusted hazard ratios (aHRs) and 95% CIs. Over a median of 15.8 years, 59 patients with NAFLD died (5.5/1,000 person-years [PY]) compared to 36 population controls (0.7/1,000 PY; difference = 4.8/1,000 PY; multivariable aHR 5.88; 95% CI 3.77–9.17), corresponding to 1 additional death per 15 patients with NAFLD, followed for 20 years. The 20-year absolute risk of overall mortality was 7.7% among patients with NAFLD, and 1.1% among controls (difference = 6.6%; 95% CI 4.0–9.2). Findings persisted after excluding those who died within the first 6 months (aHR 4.65; 95% CI 2.92–7.42), and after using full-sibling comparators (aHR 11.72; 95% CI 3.18–43.23). Simple steatosis was associated with a 5.26-fold higher adjusted rate of mortality compared to controls (95% CI 3.05–9.07), and this was amplified with NASH (aHR 11.51, 95% CI 4.77–27.79). Most of the excess mortality was from cancer (1.67 vs. 0.07/1,000PY; aHR 15.60; 95% CI 4.97–48.93), liver disease (0.93 vs. 0.04/1,000PY; aHR 16.46; 95% CI 2.75–98.43) and cardiometabolic disease (1.12 vs. 0.14/1,000PY; aHR 4.32, 95% CI 1.73–10.79). Swedish children and young adults with biopsy-confirmed NAFLD have significantly higher rates of overall, cancer-, liver- and cardiometabolic-specific mortality compared to matched general population controls. Currently, the natural history and long-term risk of mortality in children and young adults with biopsy-confirmed non-alcoholic fatty liver disease (NAFLD) is unknown. This nationwide cohort study compared the risk of all-cause and cause-specific mortality in pediatric and young adult patients in Sweden with biopsy-confirmed NAFLD to matched general population controls. We found that compared to controls, children and young adults with biopsy-confirmed NAFLD and NASH have significantly higher rates of overall, cancer-, liver- and cardiometabolic-specific mortality. [Display omitted] • Biopsy-proven pediatric and young-adult NAFLD contributes to substantial excess mortality. • Mortality is increased with simple steatosis, and further amplified with steatohepatitis. • This excess mortality was primarily from cancer, cardiometabolic disease and liver disease. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly NAFLD) is the fastest growing cause of hepatocellular carcinoma (HCC) worldwide. However, whether family members of individuals with MASLD also share an increased risk of developing HCC is unknown. This nationwide multigenerational cohort study involved family members of all Swedish adults diagnosed with biopsy-proven MASLD (1969−2017), and matched general population comparators. Using the Swedish Multi-generation Register, we identified 38,018 first-degree relatives (FDRs: parents, siblings, offspring) and 9,381 spouses of patients with MASLD, as well as 197,303 comparator FDRs and 47,572 comparator spouses. We used Cox proportional hazards models to calculate adjusted hazard ratios (aHRs) for HCC, major adverse liver outcomes (cirrhosis, decompensated liver disease or liver transplantation), liver-related mortality, extrahepatic cancer, and non-liver-related mortality. Over a median of 17.6 years, the rate of the primary outcome HCC was higher in MASLD FDRs vs. comparator FDRs (13 vs. 8/100,000 person-years [PY]; aHR 1.80, 95% CI 1.36−2.37). The HCC risk was further increased in FDRs of individuals with liver fibrosis/cirrhosis (aHR 2.14, 95% CI 1.07−4.27; P Heterogeneity = 0.03). MASLD FDRs also had higher rates of major adverse liver outcomes (73 vs. 51/100,000 PY; aHR 1.52, 95% CI 1.36−1.69) and liver-related mortality (20 vs. 11/100,000 PY; aHR 2.14, 95% CI 1.67−2.74). MASLD FDRs with any concomitant chronic liver condition experienced accelerated progression of liver disease (aHR 1.47, 95% CI 1.29-1.67). MASLD spouses were at higher risks of major adverse liver outcomes (86 vs. 74/100,000 PY; aHR 1.23, 95% CI 1.01−1.51) and liver-related mortality (25 vs. 19/100,000 PY; aHR 1.93, 95% CI 1.15−3.23), but not of HCC (aHR 1.43, 95% CI 0.87−2.35). There is distinct familial clustering of adverse liver-related outcomes in families of individuals with biopsy-proven MASLD, with higher relative risks of HCC, progressive liver disease, and liver-related mortality, but absolute risks are low. Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly termed NAFLD) clusters in families with high genetic susceptibility and shared environmental risk factors, but the risks of developing hepatocellular carcinoma and other major liver-related outcomes in family members of individuals with MASLD are largely unknown. This large nationwide multigenerational cohort study involving family members (first-degree relatives and spouses) of individuals with biopsy-proven MASLD and of matched general population comparators found slightly increased risks of hepatocellular carcinoma in first-degree relatives, and of developing cirrhosis and liver-related mortality in all family members of individuals with biopsy-proven MASLD. The findings of this study provide large-scale evidence to inform clinical practice guidelines for recommendations on the early identification of individuals at higher risk of liver-related morbidity and mortality. [Display omitted] • Nationwide multigenerational study of 292,274 family members of people with biopsy-confirmed MASLD and comparators. • MASLD first-degree relatives had increased hazards of HCC, major adverse liver outcomes and liver-related mortality. • The absolute risk of HCC was low, with only one extra case per 900 first-degree relatives over 20 years of follow-up. • Spouses of individuals with MASLD also had a higher relative risk of developing major adverse liver outcomes. • Liver disease progressed more rapidly in MASLD first-degree relatives with concomitant liver diseases. [ABSTRACT FROM AUTHOR]