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Puoti. Hepatoma Res 2018;4:57 I http://dx.doi.org/10.20517/2394-5079.2018.67 Page 5 of 11

According to data from the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database
between 2004 and 2009, NAFLD represented the third most common cause of HCC, after hepatitis C and
[36]
alcohol-related disease, diagnosed in 14.1% of patients with HCC . During the six-year study period, an
average annual increase of 9% was reported in patients with NAFLD, compared with a 13% increase in
patients with hepatitis C.

In a United States population-based study, NAFLD was classified as the most common risk factor for the
[37]
development of HCC (59%) with a cumulative incidence of 0.3% over a 6-year follow-up . In another
prospective community-based study which evaluated the outcomes of patients with NASH and cirrhosis,
[38]
11.3% of patients developed HCC after a mean follow-up of 7.6 years .
As to the prevalence of NAFLD in patients with HCC, several studies showed that steatosis at present does
surpass HCV and HBV as the first cause of HCC, ranging from 25% to 35% of all cases.

Moreover, other studies reported development of HCC in non cirrhotic NASH liver [39,40] . Thus, it is not
surprising that NAFLD is the most rapidly increasing indication for liver transplantation (LT) due to HCC.

[41]
Beyond advanced liver disease itself , several other factors might interact to increase the risk of HCC in
patients with NAFLD, as follows: (1) type 2 diabetes; (2) obesity; (3) genetic background; and (4) co-factors
(HBV, HCV, alcohol abuse).

ALCOHOL AND HCC
The relationship between alcohol-related cirrhosis and HCC is now well defined. Alcohol abuse is not only
one relevant cause of chronic liver disease and cirrhosis, but strongly interacts with other causes of liver
damage, such as HBV and HCV, worsening the progression of the disease and the development of HCC.

The risk of alcohol-related HCC depends upon several factors, as age, gender (more pronounced among
females), duration and quantity of alcohol consumption. The 10-year cumulative risk of HCC in patients
[42]
with alcoholic cirrhosis ranges from 7% to 30% .

Although quantity and duration of alcohol consumption have been associated with ALD progression [43]
[44]
and an increased risk for developing HCC , not all patients who chronically overconsume alcohol develop
alcoholic cirrhosis and/or HCC. Instead, progression to ALD is influenced by the interaction between
consumption and a constellation of host factors, leading to the development of cirrhosis and HCC in only
a subset of patients. In other words, although the threshold for development of alcohol-related chronic liver
disease is well established (> 30 alcohol units for men and > 20 alcohol units for women), it has not been yet
[42]
defined the duration/quantity theshold above which the risk for HCC is strengthened .
Probably, other factors might accelerate the progression toward the HCC: genetic factors, ethnicity, first-pass
metabolism, volume of distribution, and gastric alcohol dehydrogenase kinetics.

RISK OF HCC AND SURVEILLANCE
According to International Guidelines [1,2,4,5,8] , several groups of patients are considered to have a higher risk
of developing HCC, and in these people a strict 6-mo surveillance is mandatory, as follows: (1) cirrhotic
patients of any etiology, regardless of Child-Pugh class; (2) non cirrhotic patients with chronic hepatitis B;
(3) inactive hepatitis B carriers with viraemia > 2000 UI/mL (evidence 3b, strength B for Western patients;
evidence 1b, strength A for Asian patients); (4) non cirrhotic patients with chronic hepatitis C and liver
fibrosis ≥ F3 Metavir, or ≥ 10 kpa at transient elastography (evidence 5, strength D for Western patients;