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Page 10 of 13 Farrell et al. Hepatoma Res 2020;6:18 I http://dx.doi.org/10.20517/2394-5079.2019.019

promoter mutations that can be found in low and high grade dysplastic lesions, and in increased frequency
in early HCC [62-64] . The TM6SF2 genetic variant on chromosome 19 has also been shown to be associated
with an increased risk of NAFLD and NAFLD-related hepatic fibrosis and cirrhosis, independent of other
[65]
known traditional risk factors including PNPLA3 status . In one cohort of 99 biopsy-confirmed HCC
patients, homozygous carriage of the TM6SF2 rs58542926 minor allele was associated with an increased
risk of NAFLD-related HCC. However, this was not shown to be significant on multivariate analysis when
[66]
adjusting for traditional risk factors such as age, gender or cirrhosis . Further investigation is required to
determine the clinical significance of these associations and establish whether they may be of prognostic
or diagnostic significance in the future. Consideration of cost, access to and acceptability of genetic
sequencing as a screening or prognostic tool for patients with NAFLD must also be explored.

Should patients with NAFLD undergo HCC surveillance?
Routine HCC surveillance is recommended for all patients with cirrhosis regardless of the aetiology of
their liver disease [9,10] , and as such all patients with NAFLD cirrhosis should be enrolled in a screening
program. While HCCs that are detected by surveillance programs are found at an earlier stage than those
found incidentally, patients with NAFLD-related HCC are less likely to have recognised liver disease,
and as such have a lower proportion of HCCs detected through screening compared with other causes
of liver disease . In the UK Newcastle cohort and the HCC NAFLD Italian groups, only 22.8%-47.6% of
[67]
NAFLD-related HCC cases were detected during surveillance compared with 46.2%-63.3% in HCV [34,49] .
Additionally, even in high risk patients who have NAFLD cirrhosis, screening is less likely to detect early
stage HCCs compared with other aetiologies [34,37,49] . This is likely attributable to the current recommended
screening modality of ultrasound, which can be technically challenging in obese patients with excess
[68]
visceral adiposity, and is highly operator dependant . Cross-sectional imaging such as MRI may be used
as an alternative in patients in whom adequate views of the liver are unable to be obtained via ultrasound,
however the suitability and cost-effectiveness of this approach has yet to be determined. Concern remains
regarding whether NAFLD patients without cirrhosis should also be screened, considering that 23%-54%
of NAFLD-related HCC occurs in non-cirrhotic patients. However, due to the large volume of NAFLD
patients and low annual HCC incidence of less than 2% in this cohort, routine screening is not currently
recommended [34,36,37,49] . The development of risk stratification tools may be of use in identifying high-risk
patients who would benefit from screening, and may include the use of genetic markers.

Limitations in current estimates and Future directions
While these observational studies are informative in reviewing trends, there are several limitations to this
method of determining the true burden of disease. The largest cohorts have typically identified NAFLD
using coded registry data, or blood tests, which can be inconsistent and will not always reflect whether
there is underlying fibrosis or steatohepatitis. Additionally, HCC registry information tends to be more
representative of tertiary care and patients who have been referred for active management. As NAFLD-
related HCC patients tend to be older and more comorbid, it is possible that not all cases are referred to
these specialist centres, and they may have remained in community care settings. Similarly, as the SEER
cohort demonstrated, patients with NAFLD-related HCC are less likely to be transplanted compared to
HCC due to other causes, thus transplant registry information is also likely to underestimate the true
burden of disease. Another limitation of cross-sectional retrospective studies is the evolving nature of
NAFLD and NASH. These are not static disease states, but can progress or regress over time with changes
in weight, which is often difficult to assess. While these studies have examined the risk associated with
NAFLD alone, the increasing prevalence of obesity and diabetes in HCC of all aetiologies suggests that
[34]
these metabolic factors including NAFLD could be an important co-factor in hepatic carcinogenesis .
In the future, the development of a simple, cost-effective population-based diagnostic test would be of
benefit to improve the detection rate of NAFLD and trigger screening for underlying fibrosis and cirrhosis.
Additionally, the development of prognostic markers or algorithms to identify high-risk patients for HCC
surveillance is also an area of ongoing research. Further, as treatment for NAFLD progresses, and weight