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Puoti. Hepatoma Res 2018;4:57 I http://dx.doi.org/10.20517/2394-5079.2018.67 Page 3 of 11

[1]
chronic liver disease are overlapping . From a clinical point of view, it means that most of these patients do
suffer from three different diseases at the same time, the cirrhosis and the cancer.

In the past morbidity and mortality in cirrhosis were mainly determined by other complications of the
disease, such as hepatic encephalopathy, upper digestive bleeding from esophageal varices, spontaneous
bacterial peritonitis, hepatorenal syndrome. This is mainly due to both early diagnosis and optimized
treatment of non-oncologic complications, that increasing life expectancy might be in parallel with the
[6]
increasing incidence of HCC . A significant cohort effect exists, as highest age-specific rates occur among
[7]
persons aged 75 or older .

The most common causes of HCC in the Western countries are nonalcoholic fatty liver disease (NAFLD)/
NASH, HCV infection, followed by alcohol abuse, mixed viral hepatitis plus alcohol abuse, and HBV infec-
tion [1,7-9] . Indeed, previous epidemiological studies have clearly shown that the prevalence and incidence of
HCC significantly differ in developing countries vs. developed countries, as In Eastern Asia and Middle
Africa the age-adjusted incidence rate ranges from 20 to 28 cases per 100,000 in men, while this is less than
[10]
five per 100,000 in Northern Europe, Australia and America . More in detail, among risk factors in western
countries (Europe, America), HCV infection accounts for 60%-70%, HBV for 10%-15%, alcohol for 20% and
other risk factors (NASH, hemochromatosis, etc.) for the remaining 10%. By contrast, in several areas of Asia
and Africa, HBV infection is the higher risk factor (up to 70%), while HCV, alcohol and NASH represent less
than 10%-20%.

The annual incidence of HCC in HBV cirrhotics exceeds 2%, while in chronic carriers without cirrhosis
the incidence varies between 0.4% and 0.6%, according to gender, age, viral load, geographic area [8,11,12] .
In patients with hepatitis C virus (HCV) infection the increased risk do coincide with the development
of cirrhosis, when the yearly incidence varies between 3% and 8% [13-15] . In patients with genetic
hemochromatosis the annual incidence of HCC following establishment of cirrhosis has been calculated to
be up to 5% [3,16] . From a clinical point of view, it has been clearly shown that once the cause of liver damage
[8]
has been removed, the incidence of HCC decreases, although it is not fully eliminated .

HBV AND HCC
Although rather uncommon, HCC may develop in subjects with chronic HBV infection even in the absence of
cirrhosis. In patients with HBV-related cirrhosis, the risk of HCC directly correlates with the degree of serum viral
load (serum HBV DNA levels), with the adjusted hazard ratio higher in persons with HBV DNA > 10 cp/mL than
5
4
in those with HBV DNA levels < 10 cp/mL. It has been clearly shown that the eradication or suppression of
the HBV replication by interferon or analogues nucleos(t)ides, significantly reduces, although not eliminate,
the risk of HCC in patients with cirrhosis. Antiviral treatment also decreases the risk of hepatic events, liver-
related and all-cause mortality over a 5-year observation period, particularly among those with maintaned
viral suppression [17-19] .

Several factors seem to increase HCC risk among HBV carriers: demographic (male gender, older age,
ethnicity, family history of HCC), viral (high viral load, genotype, longer duration of infection, co-infection
with HCV, HIV or HDV), clinical (cirrhosis) and environmental (exposure to aflatoxin, heavy alcohol abuse
or cigarette smoking). It has been widely reported that chronically infected males have a higher risk of
developing HCC if compared to females (2:1 to 3:1) [20,21] while in developed countries, HCC is rare in patients
[20]
under 40 years .

One could conclude that: (1) the natural history of chronic hepatitis B is dramatically improved by antiviral
treatment; (2) prevention of HCC is not achieved in the absence of stable viral suppression; (3) patients with
stable viral suppression show lower rates of hepatic decompensation as well as liver-related mortality and