The Role of Liver Fibrosis and Cirrhosis In
The Development of Primary Liver Cancers:
A Comprehensive Review
Ian Y.H. Chua
1, 2, 3, 4
20 February 2025
Abstract
Liver cancer, comprising various malignancies such as hepatocellular carcinoma (HCC),
intrahepatic cholangiocarcinoma (ICC), hepatic angiosarcoma, and hepatoblastoma,
poses a signicant global health burden. This paper investigates the relationship
between liver brosis, cirrhosis, and the incidence of primary liver cancers. The analysis
shows that approximately 75-85% of HCC cases are associated with brosis or cirrhosis,
with an annual incidence ranging from 1-8% in cirrhotic patients. In contrast, 30-50% of
ICC cases occur in the presence of underlying liver disease, while hepatic angiosarcoma
and hepatoblastoma demonstrate minimal or no association with brosis. The data
underscores the critical importance of early detection and management of liver brosis
to reduce liver cancer risk. This review consolidates ndings from peer-reviewed studies,
providing a comprehensive understanding of brosis-related carcinogenesis in liver
malignancies. Important FAQ’s are also presented in the Appendix.
Introduction
Liver cancer encompasses a range of malignancies originating from various hepatic
tissues, with hepatocellular carcinoma (HCC) being the most prevalent. The
development of liver cancer is intricately linked to underlying liver conditions, particularly
liver brosis and cirrhosis. This paper examines the relationship between liver brosis,
cirrhosis, and the incidence of dierent types of liver cancer, supported by data from
peer-reviewed studies.
1. Hepatocellular Carcinoma (HCC):
HCC accounts for approximately 75-85% of primary liver cancer cases. Chronic liver
diseases leading to brosis and cirrhosis are signicant risk factors for HCC
development. Studies indicate that up to 90% of HCC cases occur in individuals with
cirrhosis, irrespective of the underlying cause [1]. The annual incidence of HCC in
cirrhotic patients varies between 1-8%, inuenced by factors such as hepatitis B or C
infections, alcohol-related liver disease, and non-alcoholic steatohepatitis (NASH) [2].
2. Intrahepatic Cholangiocarcinoma (ICC):
ICC, arising from the bile ducts within the liver, constitutes about 10-15% of primary liver
cancers. The association between ICC and liver brosis or cirrhosis is less pronounced
than with HCC. However, studies have reported that a signicant proportion of ICC cases,
ranging from 30-50%, occur in patients with underlying liver diseases, including cirrhosis
and chronic hepatitis [3]. Risk factors such as primary sclerosing cholangitis and liver
uke infections are also implicated in ICC development.
3. Hepatic Angiosarcoma:
Hepatic angiosarcoma is a rare and aggressive malignancy, accounting for less than 2%
of primary liver cancers. Unlike HCC and ICC, hepatic angiosarcoma is not commonly
associated with liver brosis or cirrhosis. Instead, its development has been linked to
environmental exposures, such as vinyl chloride and thorium dioxide, rather than pre-
existing liver conditions [4].
4. Hepatoblastoma:
Predominantly aecting the pediatric population, hepatoblastoma represents
approximately 1% of all liver cancers. This malignancy is typically not associated with
liver brosis or cirrhosis. Genetic conditions, including familial adenomatous polyposis
and Beckwith-Wiedemann syndrome, have been identied as risk factors for
hepatoblastoma [5].
5. Overall Association Between Liver Fibrosis, Cirrhosis, and Liver Cancer:
Aggregating data across various studies, it is evident that a substantial proportion of liver
cancers develop in the context of liver brosis or cirrhosis. Approximately 70-90% of HCC
cases are associated with cirrhosis [1], while 30-50% of ICC cases occur in patients with
underlying liver diseases [3]. In contrast, malignancies such as hepatic angiosarcoma
and hepatoblastoma have a weaker or no association with liver brosis or cirrhosis.
6. Summary of Data
The data reported in this paper are summarised in Table 1.
Table 1: Percentage of Dierent Types of Liver Cancer Associated With Fibrosis
Conclusion
The presence of liver brosis and cirrhosis signicantly elevates the risk of developing
certain types of liver cancer, notably HCC and, to a lesser extent, ICC. Understanding the
etiological link between chronic liver disease and liver cancer underscores the
importance of early detection and management of liver brosis and cirrhosis to mitigate
cancer risk. Further research is warranted to elucidate the mechanisms driving
carcinogenesis in brotic livers and to develop targeted preventive strategies.
Acknowledgments
This paper was developed with the assistance of ChatGPT 4.0, which provided insights and renements in the
articulation of philosophical and scientic concepts.
1
Founder/CEO, ACE-Learning Systems Pte Ltd.
2
M.Eng. Candidate, Texas Tech University, Lubbock, TX.
3
M.S. (Anatomical Sciences Education) Candidate, University of Florida College of Medicine, Gainesville, FL.
4
M.S. (Medical Physiology) Candidate, Case Western Reserve University School of Medicine, Cleveland, OH.
References
1. Asrani, S.K., Devarbhavi, H., Eaton, J., & Kamath, P.S. (2019). Burden of liver
diseases in the world. Journal of Hepatology, 70(1), 151-171.
2. Mittal, S., & El-Serag, H.B. (2013). Epidemiology of hepatocellular carcinoma:
consider the population. Journal of Clinical Gastroenterology, 47(Suppl), S2-S6.
3. Banales, J.M., Cardinale, V., Carpino, G., et al. (2016). Expert consensus
document: Cholangiocarcinoma: current knowledge and future perspectives
consensus statement from the European Network for the Study of
Cholangiocarcinoma (ENS-CCA). Nature Reviews Gastroenterology &
Hepatology, 13(5), 261-280.
4. Koyama, T., & Fletcher, J.G. (2010). Imaging of nontraumatic hepatic
emergencies. Radiologic Clinics of North America, 48(2), 311-330.
5. Allison, D.C., & Graham, R.P. (2019). Hepatoblastoma and pediatric
hepatocellular carcinoma: an update. Surgical Pathology Clinics, 12(2), 445-464.
Appendix:
Frequently Asked Questions (FAQ’s)
Question 1: Does Cirrhosis always accompany brosis?
Yes, cirrhosis always involves brosis, but not all brosis progresses to cirrhosis.
Understanding the Relationship:
1. Fibrosis:
o Fibrosis is the accumulation of scar tissue in the liver due to chronic
injury or inammation (e.g., from viral hepatitis, alcohol, or fatty liver
disease).
o It progresses in stages (F0 to F4):
▪ F0: No brosis
▪ F1-F3: Mild to advanced brosis
▪ F4: Cirrhosis
2. Cirrhosis (Stage F4 Fibrosis):
o Cirrhosis is the end stage of brosis, characterized by extensive
scarring and regenerative nodules that distort liver architecture.
o It represents severe, widespread brosis with signicant impact on liver
function and blood ow.
o Unlike earlier brosis, cirrhosis may be irreversible, although early-
stage cirrhosis can sometimes stabilize or regress if the underlying cause
is treated.
3. Key Dierences:
o Fibrosis: Can be localized and may not signicantly impair liver function
in early stages.
o Cirrhosis: Involves diuse brosis that disrupts liver structure and
function, leading to complications like portal hypertension and liver
failure.
4. Does Cirrhosis Occur Without Fibrosis?
o No. Fibrosis is a prerequisite for cirrhosis.
o Cirrhosis is essentially advanced brosis with architectural distortion.
Cirrhosis cannot occur without brosis. It represents the nal and most severe stage
of liver brosis, where extensive scarring leads to loss of normal liver architecture and
function.
Question 2: Does only Stage F4 of brosis could lead to liver cancer
No, liver cancer—particularly hepatocellular carcinoma (HCC)—can develop not only
from stage F4 brosis (cirrhosis) but also from earlier brosis stages (F2-F3), and in some
cases, even without brosis. However, the risk increases signicantly with advanced
brosis (F3) and cirrhosis (F4).
Fibrosis Stages and Liver Cancer Risk:
1. Early Fibrosis (F0-F2):
o Minimal to moderate brosis has a low risk of progressing to liver
cancer.
o Patients with chronic hepatitis B (HBV), however, can develop
hepatocellular carcinoma (HCC) without signicant brosis due to the
direct oncogenic eects of the virus.
o Some NAFLD/NASH patients with no or mild brosis may still develop
HCC, particularly if they have metabolic syndrome.
2. Advanced Fibrosis (F3):
o Bridging brosis (F3) signicantly increases the risk of HCC.
o Studies show that F3 patients can have an annual HCC incidence of
around 1%, lower than cirrhosis but still noteworthy.
o Surveillance may be recommended in patients with high-risk conditions
(e.g., HCV with F3 brosis).
3. Cirrhosis (F4 Fibrosis):
o Cirrhosis (F4) carries the highest risk for HCC development.
o The annual incidence in cirrhotic patients ranges from 1-8%, depending
on etiology (HBV, HCV, alcohol, NASH).
o Cirrhosis disrupts liver architecture and promotes a pro-carcinogenic
environment with chronic inammation, oxidative stress, and genetic
mutations.
Question 3: When Could Liver Cancer Occur Without Reaching Stage F4 Fibrosis?
• HBV Infection:
o HBV integrates into the host genome, triggering direct carcinogenesis
without brosis or cirrhosis.
• Fibrolamellar HCC:
o Occurs in young patients without liver disease or brosis.
• NAFLD/NASH and Metabolic Syndrome:
o Obesity, diabetes, and metabolic factors can lead to HCC without
advanced brosis.
While stage F4 brosis (cirrhosis) poses the greatest risk for liver cancer, HCC can
develop at earlier brosis stages (F3) and, in certain conditions (e.g., chronic HBV,
NAFLD), even without signicant brosis. The risk escalates with advancing brosis,
which is why early detection and brosis management are crucial in liver cancer
prevention.
