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

Abstract: 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.