This document discusses risk factors for hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C virus (HCV) infection. It notes that HCV typically leads to chronic infection in over 60% of patients and cirrhosis may develop over 20 years. The risk of HCC increases with cirrhosis development. Factors like alcohol use, HIV/HBV co-infection, and hepatitis B core antibody positivity can further increase HCC risk. Non-invasive screening tools and risk scores are useful to monitor at-risk patients and prioritize them for HCC surveillance.

1. Risk Assessment for
Hepatocellular
Carcinoma Development in
Patients with Chronic
Hepatitis C
Bui Dac Chi,MD
Medic Center

2. • The prognosis of HCC is deemed poor
unless the cancer is detected and treated
at an early stage. Thus, the assessment of
risk for HCC development is essential in
the management of patients with chronic
liver diseases.

3. HCV infection typically progresses to chronic infection in more than 60% of
patients, and it can lead to cirrhosis in as many as 20% over a 20-year
period. Serum aminotransferase levels reflecting hepatocellular injury can
fluctuate, as does the viral load.
As the disease evolves, hepatocytes are progressively destroyed and replaced
by fibrosis, insidiously leading to the development of bridging fibrosis and
ultimately cirrhosis. The course of any individual patient is affected by
various factors, such as age at onset of infection, sex, co-infection with
other viruses (hepatitis A virus, HBV or HIV), or other medical conditions, as
well as risk behavior, such as alcohol consumption. Interferon-based
treatment has a varying success rate in clearing the virus, The risk of
developing HCC in chronic HCV patients with cirrhosis is as high as 4% per
year. . Although successful treatment with interferon-based regimens is
associated with a lower rate of liver-related complications or mortality, and
perhaps even regression of fibrosis/cirrhosis, patients may still be at risk of
development of HCC, even years after SVR.

4. Lauer and Walker, 2001
Normal
liver
Acute
infection
Chronic
infection
develops
in 80%
Chronic
hepatitis
Cirrhosis
develops
in 20%
Risk of
carcinoma,
1-4%
per year
≤ 20 years
Alcohol use, coinfection
≥ 30 years
Female, young age at infection
Slow
Fast
Rateofprogression
Natural History of HCV Infection:Natural History of HCV Infection:
Individual VariabilityIndividual Variability

5. • Educating patients regarding the natural
history of chronic HCV is one of the most
important things that a physician can do
for a patient with recently diagnosed
chronic HCV.

6. A warning that cirrhosis has developed
and that the risk of complications (such
as hepatocellular carcinoma) has
increased considerably.

7. • In patients with HCV, the risk for HCC increases with the development of
cirrhosis. The risk for HCC in patients with only bridging fibrosis may be <
1% per year. Some patients with HCV who develop HCC in the absence of
cirrhosis may also have occult HBV infection. Patients with HCV are more
likely to present with multiple hepatic tumors than are patients with HBV]
HCV/HBV coinfection, HCV/HIV coinfection, and concomitant diabetes
mellitus increase the risk for HCC. Suppression of viral replication with
antiviral treatments may not eliminate the risk for HCC in patients with HCV
cirrhosis] Routine screening should continue even if a sustained viral
response is attained after antiviral treatment. Cirrhosis of any cause carries
a risk for development of HCC; hemochromatosis, alcoholic liver disease,
nonalcoholic fatty liver disease, autoimmune hepatitis, primary biliary
cirrhosis, and Wilson disease have all been associated. Additional risk
factors for HCC in patients with cirrhosis include male sex, age older than
40 years, past or present obesity, diabetes mellitus, nonalcoholic fatty liver
disease, cigarette smoking, a family history of HCC, exposure to aflatoxin,
and hepatic venous outflow obstruction.

8. • Genetic Risk of Hepatocellular
Carcinoma in Patients With Hepatitis C
Virus

9. • Single nucleotide polymorphisms of
CCND2, RAD23B, GRP78, CEP164,
MDM2, and ALDH2 genes were
significantly associated with development
and recurrence of HCC in patients with
HCV.

10. IL28B minor allele is associated with a
younger age of onset of hepatocellular
carcinoma in patients with chronic
hepatitis C virus infection

11. • All HCV patients should be screened to
exclude cirrhosis by TE if available. Serum
biomarkers can be used in the absence of
TE • HCV patients who were diagnosed
with cirrhosis based on non-invasive
diagnosis should undergo screening for
HCC and PH and do not need
confirmatory liver biopsy

13. • The parameters included are commonly
recorded in clinics, which indicate that the
scoring system could be used routinely in
the clinic. The clinical practice.

14. • Calculation of Laboratory Liver Fibrosis Indices
The following values were obtained through serum sample
analysis: aspartate aminotransferase (AST), alanine
aminotransferase (ALT), gamma-glutamyl
transpeptidase (GGTP), platelet count, and cholesterol.
The APRI [18] was calculated as (AST [IU/L] / upper limit
of normal AST [IU/L]) × 100 / platelet count [109/L]. The
FIB-4 index [19, 20] was calculated as AST [IU/L] × age
[years]/ platelet count [109/L] × ALT [IU/L]1/2. The Forns
index [21] was calculated as 7.811–3.131ln(platelet
count [109/L]) + 0.781ln(GGT [IU/L]) + 3.467.ln(age)–
0.014 (cholesterol [mg/dL]).

18. • TE could be useful to identify patients at
risk of developing HCC.
• high LS value measured by TE is
significantly associated with
• the risk of presence of HCC.

21. • Finally, it has been recently suggested that SS
could predict the occurrence of complications .
Thus the potential of LS values for predicting
clinical outcomes seems to be greater than that
of liver biopsy, probably LS measures ongoing
pathophysiological processes and functions that
a biopsy cannot. Similarly, serum biomarkers
such as FibroTest , ELF ], APRI and FIB-4
[222,331], as well as for models based on
standard laboratory tests] have been shown to
have prognostic value in various chronic liver
diseases.

22. • As we know, SVR of HCV could reduce the risk
of HCC. For the high risk patients who did not
achieve SVR before, we have to do more effort
to eradicate the HCV virus in order to reduce
HCC. In patients who could not achieve SVR or
who are still within high risk category even after
SVR, selection of an intensive HCC surveillance
program is important to early detect HCC,
followed by early treatment which could increase
patients’ survival.

23. • CHC patients who respond to peg-IFN
combination therapy should be followed
even after HCV eradication, and special
attention should focus on those who have
severe liver fibrosis (F3 or F4), those with
low pre-treatment platelet levels
(,150 ﾗ 109/L) and those who are aged
≥60 years, to detect potentially treatable
HCC.

24. • The most important long-term HCC risk
predictors for chronic hepatitis B patients
are serum levels of HBV DNA, HBsAg and
alanine aminotransferase (ALT), HBeAg
serostatus, HBV genotype, HBV basal
core promoter A1762T/G1764A mutant,
gender, age, family HCC history, habitual
alcohol consumption, and co-infection with
HCV or HIV.

25. The long-term HCC risk predictors for
chronic hepatitis C patients include
increasing age, cirrhosis status, HCV
genotype 1, elevated serum levels of HCV
RNA and ALT and co-infection with HBV.

26. • Role of occult hepatitis B virus infection in chronic
hepatitis C.
In everyday clinical practice,
the detection of anti-hepatitis B core antibody (anti- HBc)
in serum of HBsAg-negative subjects is used as a
surrogate marker to identify patients with OBI.
In patients with chronic hepatitis C (CHC), OBI has been
identified in nearly one-third of these cases.
Considerable data suggest that OBI favors the increase
of liver damage and the development of hepatocellular
carcinoma (HCC) in patients with CHC.

27. • Anti-HBc-positive results on serologic
testing are a marker of high risk for HCC
among patients with HCV-related
cirrhosis. Interferon therapy might be less
effective in preventing HCC among
patients with chronic hepatitis C who are
anti-HBc-positive than in those with
chronic hepatitis C who are anti-HBc-
negative.

29. • MEDIC Researchers Develop Risk
Scores to Prioritize Individuals for
Population-wide Hepatocellular
Carcinoma Screening Using Liver
Ultrasound