Introduction: Non-alcoholic fatty liver disease is strongly associated with type-2 diabetes mellitus, with diabetic patients being at higher risk for adverse outcomes. The aim of this thesis was to explore in detail the clinical and metabolic phenotype of diabetics screened for NAFLD in primary care and to develop a referral management pathway for this population. Moreover, this thesis investigated the impact of alterations of the gut-liver axis on the severity of liver disease in such cohort.
Methods: In this cross-sectional study, consecutive diabetic patients from primary care were screened for liver disease and NAFLD. Nuclear magnetic resonance and liquid chromatography-mass spectrometry were used to explore the metabolic profile of the patients against severity of liver disease. Stool meta-taxagenomics allowed for the analysis of the composition of the microbiome, while gut permeability was investigated using an in-vitro model and an ex-vivo measurement of faecal protease activity. Inflammatory cytokines profile was also analysed in serum as well as in faecal samples.
Results: Clinically significant NAFLD was highly prevalent in the diabetic population in primary care. According to the results of this study, applying FIB-4 with a cut-off of 1.3 in this population would miss up to 38% of the patients with significant liver disease. The BIMAST score, which was derived based on simple clinical parameters, was validated both internally and externally, outperformed conventional screening methods and optimised risk-stratification in primary care. Among the metabolites, only lysine deficiency was associated with increased hepatic collagen content. Moreover, specific changes in gut microbiome were associated with more severe liver disease, while intestinal permeability tended to increase with liver disease severity. A combination of host and microbiota-related factors were associated with a leakier gut in this population.
Conclusions: Current risk-stratification for NAFLD among diabetics in primary care can be improved. Exploring the gut-liver axis may offer diagnostic as well as therapeutical insights in this population.