NON-ALCOHOLIC FATTY LIVER DISEASE IN OBESITY AND ALSTRÖM SYNDROME, AN ULTRA-RARE GENETIC MODEL FOR METABOLIC DISEASE

Introduction Non-Alcoholic Fatty Liver Disease (NAFLD) is one of the main comorbidities in patients with obesity (PwO). Alstrӧm syndrome (ALMS) is an ultra-rare monogenic disease representing a model of metabolic disease characterized by obesity, type 2 diabetes mellitus (T2DM), early incidence of NAFLD and multi-organ fibrosis. Although liver biopsy is considered the gold standard for NAFLD diagnosis, it is not recommended for screening in the general population and repeated follow-up. Thus, the usage and validation of imaging techniques coupled with non-invasive tests (NITs) are strongly required. We study PwO before and after weight loss analysing NAFLD outcomes by 2D-Shear Wave Elastography (SWE) and different NITs in a short (6 months, V6m) and long-term (4 years, V4y) follow-up. Moreover, we evaluated NAFLD and NITs in patients with ALMS (PwA), analysing the different contribution of metabolic and genetic alterations in NAFLD progression. Methods 34 PwO, 18 PwA genetically characterized, and 25 controls were enrolled and underwent a complete clinical evaluation before and after bariatric surgery. Anthropometric data, biochemical parameters, inflammatory markers and fibrosis indexes [Fibrosis-4 Index (FIB-4), AST on ALT ratio (AST/ALT), AST-to-platelet ratio index (APRI)] were collected. In PwO Enhanced Liver Fibrosis test (ELF), the caspase-cleaved fragments of keratin 18 (M30 K18) and Fibroblast Growth Factor-21 (FGF21) levels were measured. Liver fibrosis and steatosis was quantified using SWE, by the estimation of liver stiffness (LS) and comparing liver and kidney parenchyma, respectively. Results Weight loss (WL) was 23.84 ± 6.10 % at V6m and 24.77 ± 6.82 % at V4y. A parallel reduction in blood glucose and triglycerides level was observed. AST/ALT ratio (p < 0.001) and APRI (p = 0.042) early improved. However, FIB-4 displayed an opposite trend with a slight improvement at V6m and a significant worsening at V4y (p=0.002). The marker of apoptosis M30 K18 was reduced only at V4y (p=0.034). ELF did not correlate with other markers nor change after WL. FGF21 level was reduced at V4y (p=0.009). The prevalence of severe steatosis in PwO decreased over time with a corresponding increase of mild steatosis (2 p=0.031). LS was reduced both at V6m and at V4y (p= 0.008). LS (p < 0.001) and steatosis (p=0.013) were higher in PwA compared with controls. In PwA LS correlated with FIB-4 (r = 0.590, p = 0.012) and age (r = 0.505, p = 0.032), while the degree of steatosis was associated with triglyceride levels (r = 0.504, p = 0.032). LS showed an increasing trend in patients affected by metabolic comorbidities (obesity and T2DM) and displayed a significant correlation with waist circumference (r = 0.624, p = 0.012), insulin resistance index (r = 0.670, p = 0.004) and glycated haemoglobin (r = 0.715, p < 0.001). Lastly, we described a new pathogenic variant of exon 8 in ALMS1. Conclusion WL obtained by bariatric surgery displayed favourable short-term and long-term effects in PwO and NAFLD. SWE and B-mode ultrasound scan represent promising tools to accurately evaluate early liver fibrosis and steatosis in PwA (adults and children) and in PwO during follow-up. M30 K18 seems the more promising fibrosis markers and FGF21 reduction could play a role in long-term improvement of liver fibrosis and steatosis in PwO. PwA displayed enhanced steatosis, an early-increased age-dependent LS that is associated with obesity and T2DM but also strictly linked with genetic alterations suggesting that ALMS1 could be involved in liver fibrogenesis. Our study underlines the utility to investigate ultra-rare diseases as a model of common diseases to identify new pathogenic pathways, novel therapeutic targets and the best diagnostic tools for complications.