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Background & aimsMore 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.MethodsWe 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.ResultsAt 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).ConclusionsIn 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.Impact and implicationsCurrently, 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.

Background Although previous evidence has suggested an increased risk of cardiovascular disease (CVD) in patients with inflammatory bowel disease (IBD), its association with arrhythmias is inconclusive. In this study, we aimed to explore the long-term risk of arrhythmias in patients with IBD. Methods and findings Through a nationwide histopathology cohort, we identified patients with biopsy-confirmed IBD in Sweden during 1969 to 2017, including Crohn's disease (CD: n = 24,954; median age at diagnosis: 38.4 years; female: 52.2%), ulcerative colitis (UC: n = 46,856; 42.1 years; 46.3%), and IBD-unclassified (IBD-U: n = 12,067; 43.8 years; 49.6%), as well as their matched reference individuals and IBD-free full siblings. Outcomes included overall and specific arrhythmias (e.g., atrial fibrillation/flutter, bradyarrhythmias, other supraventricular arrhythmias, and ventricular arrhythmias/cardiac arrest). Flexible parametric survival models estimated hazard ratios (aHR) with 95% confidence intervals (95% CIs), after adjustment for birth year, sex, county of residence, calendar year, country of birth, educational attainment, number of healthcare visits, and cardiovascular-related comorbidities. Over a median of approximately 10 years of follow-up, 1,904 (7.6%) patients with CD, 4,154 (8.9%) patients with UC, and 990 (8.2%) patients with IBD-U developed arrhythmias, compared with 6.7%, 7.5%, and 6.0% in reference individuals, respectively. Compared with reference individuals, overall arrhythmias were increased in patients with CD [54.6 versus 46.1 per 10,000 person-years; aHR = 1.15 (95% CI [1.09, 1.21], P < 0.001)], patients with UC [64.7 versus 53.3 per 10,000 person-years; aHR = 1.14 (95% CI [1.10, 1.18], P < 0.001)], and patients with IBD-U [78.1 versus 53.5 per 10,000 person-years; aHR = 1.30 (95% CI [1.20, 1.41], P < 0.001)]. The increased risk persisted 25 years after diagnosis, corresponding to 1 extra arrhythmia case per 80 CD, 58 UC, and 29 IBD-U cases over the same period. Patients with IBD also had a significantly increased risk of specific arrhythmias, except for bradyarrhythmias. Sibling comparison analyses confirmed the main findings. Study limitations include lack of clinical data to define IBD activity, not considering the potential role of IBD medications and disease activity, and the potential residual confounding from unmeasured factors for arrhythmias. Conclusions In this study, we observed that patients with IBD were at an increased risk of developing arrhythmias. The excess risk persisted even 25 years after IBD diagnosis. Our findings indicate a need for awareness of this excess risk among healthcare professionals., Author(s): Jiangwei Sun 1,*, Bjorn Roelstraete 1, Emma Svennberg 2, Jonas Halfvarson 3, Johan Sundström 4,5, Anders Forss 1,6, Ola Olén 7,8,9, Jonas F. Ludvigsson 1,10,11 Introduction Inflammatory bowel disease [...]

Background Although evidence suggests a persistently decreased risk of colorectal cancer for up to 10 years among individuals with a negative endoscopic biopsy result (i.e., normal mucosa), concerns have been raised about other long-term health outcomes among these individuals. In this study, we aimed to explore the long-term risk of inflammatory bowel disease (IBD) after an endoscopic biopsy with normal mucosa. Methods and findings In the present nationwide cohort study, we identified all individuals in Sweden with a lower or upper gastrointestinal (GI) biopsy of normal mucosa during 1965 to 2016 (exposed, n = 200,495 and 257,192 for lower and upper GI biopsy, respectively), their individually matched population references (n = 989,484 and 1,268,897), and unexposed full siblings (n = 221,179 and 274,529). Flexible parametric model estimated hazard ratio (HR) as an estimate of the association between a GI biopsy of normal mucosa and IBD as well as cumulative incidence of IBD, with 95% confidence interval (CI). The first 6 months after GI biopsy were excluded to avoid detection bias, surveillance bias, or reverse causation. During a median follow-up time of approximately 10 years, 4,853 individuals with a lower GI biopsy of normal mucosa developed IBD (2.4%) compared to 0.4% of the population references. This corresponded to an incidence rate (IR) of 20.39 and 3.39 per 10,000 person-years in the respective groups or 1 extra estimated IBD case among 37 exposed individuals during the 30 years after normal GI biopsy. The exposed individuals had a persistently higher risk of overall IBD (average HR = 5.56; 95% CI: 5.28 to 5.85), ulcerative colitis (UC, average HR = 5.20; 95% CI: 4.85 to 5.59) and Crohn's disease (CD, average HR = 6.99; 95% CI: 6.38 to 7.66) than their matched population references. In the sibling comparison, average HRs were 3.27 (3.05 to 3.51) for overall IBD, 3.27 (2.96 to 3.61) for UC, and 3.77 (3.34 to 4.26) for CD. For individuals with an upper GI biopsy of normal mucosa, the average HR of CD was 2.93 (2.68 to 3.21) and 2.39 (2.10 to 2.73), compared with population references and unexposed full siblings, respectively. The increased risk of IBD persisted at least 30 years after cohort entry. Study limitations include lack of data on indications for biopsy and potential residual confounding from unmeasured risk or protective factors for IBD. Conclusions Endoscopic biopsy with normal mucosa was associated with an elevated IBD incidence for at least 30 years. This may suggest a substantial symptomatic period of IBD and incomplete diagnostic examinations in patients with early IBD., Author(s): Jiangwei Sun 1,*, Fang Fang 2, Ola Olén 3,4,5, Mingyang Song 6,7,8, Jonas Halfvarson 9, Bjorn Roelstraete 1, Hamed Khalili 7,8,10, Jonas F. Ludvigsson 1,11,12 Introduction Inflammatory bowel disease [...]