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Best et al. Hepatoma Res 2020;6:62 I http://dx.doi.org/10.20517/2394-5079.2020.56 Page 9 of 13

bile acid composition can be related to advanced fibrosis in NASH-HCC which indicates its important role
in fibrosis-related tumorigenesis [93,94] . In obese children, an increased abundance of Lactobacillus strains
was associated with NAFLD and NASH. while in colon cancer increased Lactobacillus abundance was
[95]
related to an anti-tumor effect .
FUTURE PERSPECTIVES
In its current state, HCC biomarker research is far from fulfilling its promises. Therefore, it has to be
subject of future investigations to elucidate the role of technologies that might complement current
biomarker-based surveillance strategies. The identification of a subset of patients at the highest risk is
[96]
critical to concentrate the effort and resources of regular HCC screening . Chromosomal aberrations,
epigenetic abnormality, and changes of gene expression are involved in hepatocarcinogenesis. Besides
microbiome analysis, omics profiling (e.g., transcriptomics, proteomics, metabolomics) has been derived
using several candidate HCC risk biomarkers which could refine HCC screening by enabling individual
risk-stratified patient management. High-throughput omics technologies have been widely applied, aiming
at the discovery of candidate biomarkers. Different types of biomolecules have been explored as sources
of information to predict HCC risk. Transcriptomic dysregulations in chronic hepatopathies capture the
functional molecular status supporting carcinogenesis. Circulating nucleic acids, proteins, and metabolites
could serve as measures of molecular HCC risk. Large amounts of data on genetic and epigenetic
abnormalities, gene expression profiles, and proteomics are available. Here, bioinformatics and network
[97]
medicine increasingly play a pivotal role to organize and analyze the accumulated data . Those analyses
may facilitate the identification of a distinct niche of application for each individual biomarker.

CONCLUSION
HCC surveillance, in line with guidelines, significantly improves survival outcomes due to a higher
proportion of patients diagnosed in an earlier stage of HCC, allowing for curative treatment options.
According to most international guideline, recommendations have considered ultrasound as the method
of choice for screening. US alone lacks sensitivity in the detection of small lesions, particularly in advanced
cirrhosis and obesity , factors that are compounded by varying skill levels of investigators and available
[98]
technology. Nevertheless, numerous guidelines omitted the additional determination of AFP, despite the
fact that previous trials clearly demonstrated that the utilization of AFP or biomarker-based scores such as
GALAD complimentary to ultrasound resulted in a significant improvement in sensitivity while preserving
high level of specificity. During the past decade, several biomarkers such as AFP-L3, DCP, osteopontin,
glypican-3, and others were evaluated, however, only few markers reached longitudinal retrospective phase
III development. Widely lacking are large multinational phase IV prospective screening trials confirming
the benefit of the markers or their combinations for surveillance.

Facing increasing global HCC mortality, NASH has become a major risk factor for HCC development, even
in the absence of cirrhosis [5,99,100] , therefore the definition of the population at risk has to be redefined for
future HCC diagnostic and treatment guidelines to address this epidemiological shift. Nevertheless, cost-
effectiveness analyses do not support surveillance in the entire population with NAFLD who do not have
cirrhosis or advanced fibrosis. Here, continued efforts of risk stratification with factors such as gender and
age in conjunction with NAFLD-associated HCC risks such as PNPLA3 or TM6SF2 gene polymorphisms
or distinct alterations of the microbiome and bile acid metabolism may facilitate a more concise definition
of populations at HCC risk within this cohort.

Furthermore, diabetes mellitus needs to be recognized as an individual predisposing risk factor for HCC
development in the presence and even in the absence of concomitant NASH.