This interactive session explored whether precision medicine to manage NAFLD and find new therapies for NAFLD subtypes would be a feasible strategy.
Despite an escalating global NAFLD epidemic worldwide, pharmacological treatments for this disease have been elusive. This interactive session explored whether precision medicine to manage NAFLD and find new therapies for NAFLD subtypes would be a feasible strategy to overcome the difficulties posed by the heterogeneous nature of the disease.
The influence of genetics in NAFLD may make it possible to identify disease subtypes; PNPLA3 and LYPLAL1 seem to increase risk of liver disease but not metabolic disease, TM6SF2 appears to predispose to liver disease but may be protective against dyslipidaemia and heart disease, and GCKR increases risk of liver disease and dyslipidaemia but protects against diabetes. Application of this knowledge is the essence of precision medicine and we may not need to look too far into the future for genotype specific recommendations for PNPLA3 in terms of therapeutic management and lifestyle counselling in NAFLD. For other loci, however, more research is required.
The impact of gene–environment interactions in NAFLD were also explored, with discussions around how epigenetics contributes to its phenotypic heterogeneity. Studies into DNA methylation patterns, for example, reveal that in NAFLD, overexpression and hypomethylation of tissue repair genes lead to accumulation of scar tissue and downregulation and hypermethylation of metabolic genes lead to metabolic dysregulation. This and other tissue-specific epigenetic modifications, including regulation of non-coding RNAs and changes in the liver microbiome result in gradual loss of organ function and systemic metabolic maladaptive response. However, such modifications should be at least partially reversible, and their manipulation holds much promise in the therapeutic management of NAFLD.
Concluding the session, a fascinating presentation demonstrated the influence of the human liver lipidome on the aetiology of NAFLD. Marked differences were revealed between NAFLD associated with metabolic syndrome and that associated with a PNPLA3 risk allele, the former being associated with increased insulin-resistance causing ceramides and the latter with retention of polyunsaturated triglycerides in the liver. Genetic variants protective against NAFLD were also associated with increased hepatic phosphatidylcholines, suggesting a new mechanism for NAFLD that is now being investigated.
In an absorbing panel discussion, the speakers agreed with 77% of the audience that a combination of genetic predisposition, lifestyle-related epigenetic changes and qualitative differences in hepatic lipids is important in the progression of NAFLD. In particular, it was noted that some of the NAFLD-associated variants identified so far have high odds ratios that approach Mendelian levels and, when carriers of these alleles also have predisposing lifestyle/environmental factors, the effects are further amplified. This illustrates the potential for precision medicine to maximise outcomes from interventions for NAFLD by targeting them towards patients who would benefit the most.