**7. Conclusions**

Worldwide, NAFLD and NASH as well as NAFLD-related diseases (OSAS, PCOS, non-obese NAFLD), have emerged as leading causes of chronic liver disease in the last decades. The pathogenesis of respective diseases is complex and influenced by genetic factors, patients' characteristics, and a variety of risk factors. Although the factors and involved pathways triggering initiating and progression of NAFLD and NASH are reasonably well known, there is an urgent clinical need to establish reliable, noninvasive biomarkers, tests or algorithms that avoid the need of liver biopsy and allow to differentiate between disease stages. During the last decades, a great variety of multiparametric panels and parameter combinations (NFLS, HIS, FLI, LAP index, FLIP, CHeK, NFS, APRI, BARD, ELF, Hepascore) taking into account serum markers (e.g., ALT, AST, bilirubin, Hb1Ac, HDL, α2M, platelet counts), patient characteristics (sex, gender, BMI), or comorbidities (diabetes) were established. However, all these diagnostic panels have limitations and alone are not suitable to replace liver biopsy. Nowadays, high-resolution imaging modalities such as ultrasound, MRI, elastography, and CAP have been established. Several of these techniques, such as MRI-PDFF, which can specifically detect the presence of hepatic steatosis and assess liver fat over the entire liver, might be useful to substitute biopsies and greatly assist the objective follow-up of therapeutic trials. Finally, liver-derived exosomes released into the systemic circulation and toxic lipids are in focus as targets for biomarkers development in liquid liver biopsies.

**Author Contributions:** Conceptualization, H.K.D. and R.W.; writing—original draft preparation, H.K.D. and R.W.; writing—review and editing, H.K.D., R.W. and S.W.; visualization, S.W.; funding acquisition, R.W.

**Funding:** This research was funded by the German Research Foundation (SFB/TRR57).

**Conflicts of Interest:** The authors declare no conflicts of interest.

### **References**


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