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Page 10 of 15 Benhammou et al. Hepatoma Res 2020;6:35 I http://dx.doi.org/10.20517/2394-5079.2020.16

alcohol, NAFLD HCC screening has several challenges. Obesity, common in this patient population, has
been shown to decrease the effectiveness of ultrasound screening [127-129] . The effects of visceral adipose tissue
or intrahepatic steatosis in lesions are also unclear. The use of other imaging modalities has been proposed
including abbreviated MRI scans, which are promising given their sensitivity and specificity, although their
cost-effectiveness remains to be evaluated [130,131] .

Over the years, new biomarkers have been introduced including the Lens culinaris lectin-binding subfraction
of the AFP (AFP-L 3%) [132] and des gamma carboxyy prothrombin [133] . The clinical utility of these biomarkers
in NAFLD-associated HCC patients remains unknown. In our studies, we found that compared to hepatitis
B and C, patients with NAFLD-associated HCC were less likely to be AFP producers (AFP < 10 ng/mL)
(manuscript submitted). Due to the complex nature of NAFLD, the use of a combination of markers will
likely be more clinically relevant. This is demonstrated by Best et al.’s [134] study using the GALAD (Gender,
Age, AFP-L3, and Des-carboxy-prothormbin) score to predict early detection of NAFLD-associated HCC
cases in Europe and Japan, including the sub-group of patients without cirrhosis. These results will need to
be validated in the US patient population given the heterogeneity of NAFLD across different ethnic groups,
especially given the lower performance of the GALAD score in the sub-group of US-American cohort. Risk
stratification calculators have been developed to assess the risk of HCC and the utility of HCC screening,
including in the NAFLD patient population, however these have focused on the cirrhosis group which is at
[24]
higher risk of HCC and have not entered clinical practice yet .
Clinical practices therefore vary due to the limited data, which has prompted expert societies to provide
some guidance in the form of expert opinion [135] . In our local liver transplantation institution, we choose to
screen patients yearly with an abdominal ultrasound and blood work, especially if they have a diagnosis of
T2D.

CONCLUSIONS AND OUTSTANDING QUESTIONS
NAFLD-associated HCC is on the rise and will continue to create a large economic burden on health care,
prompting essential research. Its heterogenous clinical presentation is reflective of its complex traits with
important genetic and non-genetic, as well as environmental risk factors. Although a combination of basic,
translational and clinical research has shed some light on its distinct presentations, many questions remain
unanswered. The lack of consistent clinical definitions to identify NAFLD and NASH patients when using
electronic medical records in research over the years has made comparison between studies challenging.
This has been recognized in clinical trials where a larger effort has been made on using consistent and
reproducible definitions to identify patients and characterize responses to NASH treatment. Bigger public
health questions remain unanswered including who to screen and how to use modifiable factors such as
statins and aspirin to mitigate the risk of liver disease progression and HCC, where liver transplantation
remains scarce and not available to all patients. In the era of precision healthcare and medicine, identifying
“at-risk” populations within the larger NAFLD group will be key to tailoring screening and treatment options
and will help providers identify patients in need of close monitoring under the care of subspecialists versus
primary care. In light of the complex and heterogenous nature of the disease, identifying “at-risk” patients
will likely require a combination of clinical characteristics, biomarker discovery and risk-stratification
calculators.

DECLARATIONS
Authors’ contributions
Involved in conception of the study, drafting of the manuscript and critical revision for important intellectual
content: Benhammou JN, Hussain SK, El-Kabany M
Conducted the literature review, drafted the section on the microbiome and provided critical revision of the
manuscript for intellectual content: Lin J