Liver-related complications and metabolic comorbidities during long-term follow-up of patients with Non-Alcoholic Fatty Liver Disease

Background: Non-alcoholic fatty liver disease (NAFLD) is highly associated with the metabolic syndrome, and due to increasing prevalence of for example obesity it is now the most common liver disease in the world. A minority progress to advanced fibrosis/cirrhosis, which is associated with increased mortality, but it is not entirely clear which patients who have an increased risk of fibrosis. General aim:To describe the long-term clinical development and prognosis of biopsy-proven NAFLD, focusing on liver-related morbidity, metabolic comorbidities and mortality. Methods: In Paper 1, patients with long-term insulin resistance, a risk factor for developing NAFLD, were invited to assessment of liver function tests and if elevated patients were further examined for a diagnosis of NAFLD. In Paper 2-4, all patients with biopsy-proven NAFLD in Malmö, Sweden 1978-2006 were identified, and further assessed with an extensive review of patients’ medical files regarding long-term risk of cirrhosis development, liver-related events, metabolic comorbidities, chronic kidney disease and mortality, and the use of non-invasive fibrosis scoring system in early indentification of these risk patients. Follow-up time in all four papers were between 17-27 years. Results: Only 15% (n=25) of patients with long-term insulin resistance in Paper 1 had elevated liver function tests at long-term follow-up, and of these only 23.8% had NAFLD diagnosed with imaging. Patients with NAFLD had significantly higher prevalence of the metabolic syndrome and progressive insulin resistance (type 2 diabetes mellitus (T2DM) or impaired fasting glucose). Of all patients with biopsy-proven NAFLD included in Paper 2-4 survival was significantly lower than a reference population. The prevalence of cirrhosis at follow-up was 17%, and 13.8% developed liver-related events. Hepatocellular cancer (HCC) was diagnosed in nearly 6% of patients. The most common metabolic comorbidity at follow-up was hypertension in 66% af patients, and T2DM in 53%. NAFLD patients with advanced fibrosis (stage 3-4) had significantly higher prevalence of T2DM. Chronic kidney disease (CKD) was prevalent in 12.5% at inclusion, but only significantly higher in the highest age group (> 55 years). At follow-up 37.5% had developed CKD, however not significantly different to the reference group. NAFLD patients with long-term CKD had significantly higher mortality, which was explained by an increased prevalence of metabolic comorbidities including T2DM, not CKD per se. When calculating simple non-invasive fibrosis scoring systems (inclucing NAFLD fibrosis score and FIB-4 index) from the time of biopsy, these could with acceptable accuracy identify NAFLD patients with an increased risk of overall mortality, future liver-related events, T2DM, cardiovascular disease and CKD. Conclusions: NAFLD development in patients with long-term insulin resistance is associated with a progress of metabolic comorbidities. Of all patients with biopsy-proven NAFLD 17% developed cirrhosis and 6 % HCC at long-term follow-up. Overall mortality is significantly higher in NAFLD than in a reference population. Long-term CKD in NAFLD is associated with increased overall mortality, which is explained by metabolic comorbidities. Simple non-invasive fibrosis scoring systems can be used for early identification of NAFLD patients with increased risk of future liver-related events and overall mortality, but also of future metabolic comorbidities and CKD

Increased risk of cirrhosis and hepatocellular cancer during long-term follow-up of patients with biopsy-proven NAFLD.

Abstract Objective. Our aims were to investigate the natural history of biopsy-proven non-alcoholic fatty liver disease (NAFLD) in Sweden, its associated complications, the clinical and biochemical factors associated with more advanced liver disease and the survival rate with a mean follow-up time of 27 years. Material and methods. All subjects participating in the population-based prospective cohort study Malmö Preventive Project (MPP) from 1974 to 1992 who had undergone liver biopsy with the diagnosis of NAFLD were included. The remaining MPP cohort was used as a control group. Subjects with other liver diseases and alcohol overconsumption were excluded. A panel of blood tests was analyzed in the MPP cohort. Follow-up of the NAFLD patients included studies of medical records, pathology records and mortality rates from the Swedish National Board of Health and Welfare's register until the end of 2011. Results. A total of 36 patients were diagnosed with biopsy-proven NAFLD. Median follow-up time was 27.0 years (6.32-35.3). Nine patients (25%) were diagnosed with cirrhosis and five (14%) with hepatocellular cancer, all with a previous diagnosis of cirrhosis. There were significant differences in liver function tests, insulin resistance (as homeostasis model assessment of insulin resistance) and body mass index (BMI) in patients with NAFLD compared with the control group. Mortality in the NAFLD group was significantly higher, 58.3% compared to 33.8% (p = 0.004). Hepatocellular cancer accounted for 23.8% of all deaths in the NAFLD group, compared to 0.7% (p = 0.000). Conclusions. NAFLD can progress to advanced liver disease, including cirrhosis, with a higher than expected mortality and incidence of hepatocellular cancer

Non-invasive fibrosis scoring systems can predict future metabolic complications and overall mortality in non-alcoholic fatty liver disease (NAFLD)

BACKGROUND AND AIM: Progression to fibrosis in non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of liver-related events, overall mortality and possibly metabolic comorbidities. Our aim was to determine if non-invasive fibrosis scoring systems can predict the future risk of diabetes mellitus, cardiovascular disease (CVD), chronic kidney disease (CKD), liver-related events and overall mortality.METHODS: Patients with biopsy-proven NAFLD 1978 to 2006 were identified from a computerised register in Malmö, Sweden. Medical records were scrutinised in detail to collect data from inclusion to endpoint (death or end of 2016). Non-invasive fibrosis scoring systems (FIB-4-index, NAFLD fibrosis score (NFS), APRI and BARD score) were calculated and the scores classified into three risk categories (low, intermediate and high risk for advanced fibrosis). Chronic kidney disease was evaluated using the CKD-EPI equation.RESULTS: One hundred and forty-four patients with biopsy-proven NAFLD were included, with a mean age of 53.2 years and a mean follow-up time of 18.8 years. At inclusion, 18% had advanced fibrosis. NFS was the only score that could predict the future risk of all included outcomes with fairly good accuracy (Area-under-ROC curve). Multivariate-adjusted hazard ratios revealed that both the intermediate and high-risk category of FIB-4-index and NFS could significantly predict metabolic outcomes. All four scoring systems significantly predicted overall mortality in the high-risk category.CONCLUSIONS: Non-invasive fibrosis scoring systems, especially NFS and FIB-4-index, can be used to identify patients at risk of future liver-related events, overall mortality, metabolic comorbidities and CKD

Increased mortality in non-alcoholic fatty liver disease with chronic kidney disease is explained by metabolic comorbidities

Background: There is a close association between non-alcoholic fatty liver disease (NAFLD) and prevalent chronic kidney disease (CKD). Few longitudinal studies exist. No previous study has investigated to what extent CKD affects mortality in biopsy-proven NAFLD. Our aim was to investigate the long-term risk of developing CKD in biopsy-proven NAFLD and its effect on mortality. Methods: Patients with biopsy-proven NAFLD diagnosed in 1978-2006 in Malmö, Sweden were included. Estimated glomerular filtration rate (eGFR) at baseline and last follow-up was calculated with the CKD-EPI equation. CKD 3–5 ( 55 years, 25% vs. 9.5%, P = 0.003), and no significant difference was seen at follow-up (in total 37.5% vs. 30.8%, P = 0.124). NAFLD patients with long-term CKD had significantly higher crude overall mortality rate than NAFLD patients without CKD (P < 0.001). Regression analyses revealed that this increased mortality risk was explained by an increased prevalence of metabolic comorbidities (including diabetes mellitus), not CKD. Conclusion: Mortality risk is significantly increased in NAFLD patients with long-term CKD due to metabolic comorbidities, not influenced by CKD per se

Validation of Risk Scoring Systems in Ursodeoxycholic Acid-Treated Patients With Primary Biliary Cholangitis

INTRODUCTION: Risk stratification based on biochemical variables is a useful tool for monitoring ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC). Several UDCA response criteria and scoring systems have been proposed for risk prediction in PBC, but these have not been validated in large external cohorts. METHODS: We performed a study on data of 1746 UDCA-treated patients with PBC from 25 centers in Europe, United States, and Canada. The prognostic performance of the risk scoring systems (GLOBE and UK-PBC) and the UDCA response criteria (Barcelona, Paris I, Paris II, Rotterdam, and Toronto) were evaluated. We regarded cirrhosis-related complications (ascites, variceal bleeding, and/or hepatic encephalopathy) as clinical end points. RESULTS: A total of 171 patients reached a clinical end point during a median 7 years (range 1-16 years) of follow-up. The 5-, 10- and 15-year adverse outcome-free survivals were 95%, 85%, and 77%. The GLOBE and UK-PBC scores predicted cirrhosis-related complications better than the UDCA response criteria. The hazard ratio (HR) for a 1 standard deviation increase was HR 5.05 (95% confidence interval (CI): 4.43-5.74, P < 0.001) for the GLOBE score and HR 3.39 (95% CI: 3.10-3.72, P < 0.001) for the UK-PBC score. Overall, the GLOBE and UK-PBC risk scores showed similar and excellent prognostic performance (C-statistic, 0.93; 95% CI: 0.91%-95% vs 0.94; 95% CI: 0.91%-0.96%). DISCUSSION: In our international, multicenter PBC cohort, the GLOBE and UK-PBC risk scoring systems were good predictors of future cirrhosis-related complications